Publication
2018 |
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Journal Articles |
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| 113. | Cammarata-Mouchtouris, Alexandre; Nguyen, Xuan-Hung; Goto, Akira; Orian, Amir; Bonnay, Francois; Fauvarque, Marie-Odile; Reichhart, Jean-Marc; Matt, Nicolas Hyd ubiquitinates the NF-κB co-factor Akirin to activate an effective immune response in Drosophila Journal Article bioRxiv, 2018. @article{Cammarata-Mouchtouris323170, title = {Hyd ubiquitinates the NF-κB co-factor Akirin to activate an effective immune response in Drosophila}, author = {Alexandre Cammarata-Mouchtouris and Xuan-Hung Nguyen and Akira Goto and Amir Orian and Francois Bonnay and Marie-Odile Fauvarque and Jean-Marc Reichhart and Nicolas Matt}, url = {https://www.biorxiv.org/content/early/2018/05/16/323170}, doi = {10.1101/323170}, year = {2018}, date = {2018-05-16}, journal = {bioRxiv}, publisher = {Cold Spring Harbor Laboratory}, abstract = {Activation of inflammatory response is a tightly controlled process that is mediated by NF-kB pathways. Ubiquitinations are known to modulate the mammalian inflammatory response at all levels of the NF-kB pathways, but the mechanism involved in this ubiquitin-mediated modulation of the inflammation is still not fully understood. Here, we used Drosophila genetics to identify E3-ubiquitin ligases involved in the innate immune response and explore their conservation in mammals. To this aim, we conducted an ex-vivo RNA interference screen of the E3 ubiquitin-ligases encoded by the fruit fly genome downstream of the Drosophila IMD pathway. This screen identified Hyperplastic Discs Hyd as acting genetically at the level of the NF-kB cofactor Akirin. Drosophila lacking Hyd failed to express the full set of anti-microbial peptides coding genes and succumbed to immune challenges. Remarkably, HyD-mediated K63-polyubiquitination of Akirin is required for the efficient binding of Akirin to the NF-kB transcription factor Relish. This Hyd-mediated interaction triggers the activation of a subset of Relish target genes, required in-vivo to survive immune challenges. We show further that Urb5, the mammalian homolog of Hyd, is also required in the NF-kB pathway. This study links the action of a E3-ubiquitin ligase to the activation of immune effector genes, deepening our understanding of the involvement of ubiquitination in inflammation and identifying a potential target for the control of inflammatory diseases.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Activation of inflammatory response is a tightly controlled process that is mediated by NF-kB pathways. Ubiquitinations are known to modulate the mammalian inflammatory response at all levels of the NF-kB pathways, but the mechanism involved in this ubiquitin-mediated modulation of the inflammation is still not fully understood. Here, we used Drosophila genetics to identify E3-ubiquitin ligases involved in the innate immune response and explore their conservation in mammals. To this aim, we conducted an ex-vivo RNA interference screen of the E3 ubiquitin-ligases encoded by the fruit fly genome downstream of the Drosophila IMD pathway. This screen identified Hyperplastic Discs Hyd as acting genetically at the level of the NF-kB cofactor Akirin. Drosophila lacking Hyd failed to express the full set of anti-microbial peptides coding genes and succumbed to immune challenges. Remarkably, HyD-mediated K63-polyubiquitination of Akirin is required for the efficient binding of Akirin to the NF-kB transcription factor Relish. This Hyd-mediated interaction triggers the activation of a subset of Relish target genes, required in-vivo to survive immune challenges. We show further that Urb5, the mammalian homolog of Hyd, is also required in the NF-kB pathway. This study links the action of a E3-ubiquitin ligase to the activation of immune effector genes, deepening our understanding of the involvement of ubiquitination in inflammation and identifying a potential target for the control of inflammatory diseases. |
| 112. | Issa, Najwa; Guillaumot, Nina; Lauret, Emilie; Matt, Nicolas; Scaeffer-Reiss, Christine; Dorsselaer, Alain Van; Reichhart, Jean-Marc; Veillard, Florian The circulating protease Persephone is an immune sensor for microbial proteolytic activities upstream of the Drosophila Toll pathway. Journal Article Molecular Cell, 69 (4), pp. 539-550, 2018, ISSN: 1097-2765. @article{Issa2018, title = {The circulating protease Persephone is an immune sensor for microbial proteolytic activities upstream of the Drosophila Toll pathway.}, author = {Najwa Issa and Nina Guillaumot and Emilie Lauret and Nicolas Matt and Christine Scaeffer-Reiss and Alain Van Dorsselaer and Jean-Marc Reichhart and Florian Veillard}, url = {http://www.cell.com/molecular-cell/fulltext/S1097-2765(18)30058-3?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1097276518300583%3Fshowall%3Dtrue}, doi = {10.1016/j.molcel.2018.01.029}, issn = {1097-2765}, year = {2018}, date = {2018-02-15}, journal = {Molecular Cell}, volume = {69}, number = {4}, pages = {539-550}, abstract = {Microbial or endogenous molecular patterns as well as pathogen functional features can activate innate immune systems. Whereas detection of infection by pattern recognition receptors has been investigated in details, sensing of virulence factors activities remains less characterized. In Drosophila, genetic evidences indicate that the serine protease Persephone belongs to a danger pathway activated by abnormal proteolytic activities to induce Toll signaling. However, neither the activation mechanism of this pathway nor its specificity has been determined. Here, we identify a unique region in the pro-domain of Persephone that functions as bait for exogenous proteases independently of their origin, type, or specificity. Cleavage in this bait region constitutes the first step of a sequential activation and licenses the subsequent maturation of Persephone to the endogenous cysteine cathepsin 26-29-p. Our results establish Persephone itself as an immune receptor able to sense a broad range of microbes through virulence factor activities rather than molecular patterns.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Microbial or endogenous molecular patterns as well as pathogen functional features can activate innate immune systems. Whereas detection of infection by pattern recognition receptors has been investigated in details, sensing of virulence factors activities remains less characterized. In Drosophila, genetic evidences indicate that the serine protease Persephone belongs to a danger pathway activated by abnormal proteolytic activities to induce Toll signaling. However, neither the activation mechanism of this pathway nor its specificity has been determined. Here, we identify a unique region in the pro-domain of Persephone that functions as bait for exogenous proteases independently of their origin, type, or specificity. Cleavage in this bait region constitutes the first step of a sequential activation and licenses the subsequent maturation of Persephone to the endogenous cysteine cathepsin 26-29-p. Our results establish Persephone itself as an immune receptor able to sense a broad range of microbes through virulence factor activities rather than molecular patterns. |
2017 |
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Journal Articles |
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| 111. | Patrnogic, Jelena; Leclerc, Vincent The serine protease homolog spheroide is involved in sensing of pathogenic Gram-positive bacteria Journal Article PLoS One, 12 (12), 2017. @article{Jelena2017, title = {The serine protease homolog spheroide is involved in sensing of pathogenic Gram-positive bacteria}, author = {Jelena Patrnogic and Vincent Leclerc}, url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5718610/}, doi = {10.1371/journal.pone.0188339}, year = {2017}, date = {2017-12-06}, journal = {PLoS One}, volume = {12}, number = {12}, abstract = {In Drosophila, recognition of pathogens such as Gram-positive bacteria and fungi triggers the activation of proteolytic cascades and the subsequent activation of the Toll pathway. This response can be achieved by either detection of pathogen associated molecular patterns or by sensing microbial proteolytic activities ("danger signals"). Previous data suggested that certain serine protease homologs (serine protease folds that lack an active catalytic triad) could be involved in the pathway. We generated a null mutant of the serine protease homolog spheroide (sphe). These mutant flies are susceptible to Enterococcus faecalis infection and unable to fully activate the Toll pathway. Sphe is required to activate the Toll pathway after challenge with pathogenic Gram-Positive bacteria. Sphe functions in the danger signal pathway, downstream or at the level of Persephone.}, keywords = {}, pubstate = {published}, tppubtype = {article} } In Drosophila, recognition of pathogens such as Gram-positive bacteria and fungi triggers the activation of proteolytic cascades and the subsequent activation of the Toll pathway. This response can be achieved by either detection of pathogen associated molecular patterns or by sensing microbial proteolytic activities ("danger signals"). Previous data suggested that certain serine protease homologs (serine protease folds that lack an active catalytic triad) could be involved in the pathway. We generated a null mutant of the serine protease homolog spheroide (sphe). These mutant flies are susceptible to Enterococcus faecalis infection and unable to fully activate the Toll pathway. Sphe is required to activate the Toll pathway after challenge with pathogenic Gram-Positive bacteria. Sphe functions in the danger signal pathway, downstream or at the level of Persephone. |
| 110. | Chamy, Laure El; Matt, Nicolas; Reichhart, Jean-Marc Advances in Myeloid-Like Cell Origins and Functions in the Model Organism Drosophila melanogaster Journal Article Microbiology Spectrum, 5 (1), 2017, ISSN: 2165-0497. @article{Chamy2017, title = {Advances in Myeloid-Like Cell Origins and Functions in the Model Organism Drosophila melanogaster}, author = { Laure El Chamy and Nicolas Matt and Jean-Marc Reichhart}, url = {http://www.asmscience.org/content/journal/microbiolspec/10.1128/microbiolspec.MCHD-0038-2016}, doi = {10.1128/microbiolspec.MCHD-0038-2016}, issn = {2165-0497}, year = {2017}, date = {2017-01-01}, urldate = {2017-07-12}, journal = {Microbiology Spectrum}, volume = {5}, number = {1}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
| 109. | Koltun, Bella; Shackelford, Eliza; Bonnay, François; Matt, Nicolas; Reichhart, Jean-Marc; Orian, Amir The SUMO-targeted ubiquitin ligase, Dgrn, is essential for Drosophila innate immunity Journal Article The International Journal of Developmental Biology, 61 (3-4-5), pp. 319–327, 2017, ISSN: 0214-6282. @article{koltun_sumo-targeted_2017, title = {The SUMO-targeted ubiquitin ligase, Dgrn, is essential for Drosophila innate immunity}, author = { Bella Koltun and Eliza Shackelford and François Bonnay and Nicolas Matt and Jean-Marc Reichhart and Amir Orian}, url = {http://www.intjdevbiol.com/paper.php?doi=160250ao}, doi = {10.1387/ijdb.160250ao}, issn = {0214-6282}, year = {2017}, date = {2017-01-01}, urldate = {2017-07-12}, journal = {The International Journal of Developmental Biology}, volume = {61}, number = {3-4-5}, pages = {319--327}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
2016 |
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Books |
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| 108. | Boujard, Daniel; Leclerc, Vincent; Vincent, Stéphane Biologie du développement Book Editions Dunod, 2016, ISBN: 978-2-10-072085-9. @book{leclerc2016, title = {Biologie du développement}, author = {Daniel Boujard and Vincent Leclerc and Stéphane Vincent}, editor = {Editions Dunod}, url = {https://www.dunod.com/sciences-techniques/biologie-du-developpement}, isbn = {978-2-10-072085-9}, year = {2016}, date = {2016-06-01}, booktitle = {Biologie du développement}, pages = {304}, edition = {Editions Dunod}, crossref = {EAN: 9782100720859}, abstract = {La biologie du développement étudie les phénomènes qui permettent le passage d’un œuf à un organisme adulte. Cette discipline a beaucoup évolué ces dernières années avec l'essor des nouvelles techniques d’imagerie in vivo, des « omiques » et des techniques de transgénèse. Aux progrès technologiques s’ajoutent les avancées importantes en génétique et épigénétique, tout cela permettant d’avoir aujourd’hui une vision beaucoup plus intégrée des mécanismes fondamentaux de la biologie du développement. L’objectif de l’ouvrage est de fournir une vision synthétique et moderne de la discipline tout en montrant son lien avec la biologie cellulaire, la génétique, la physiologie et la médecine. Les principaux modèles, historiques ou émergents, sont présentés puis les grandes étapes du développement sont détaillées en s’appuyant sur les données les plus récentes. Un chapitre aborde l’importance de l’apport de la biologie du développement dans la compréhension de nombreuses pathologies, dont le cancer.}, keywords = {}, pubstate = {published}, tppubtype = {book} } La biologie du développement étudie les phénomènes qui permettent le passage d’un œuf à un organisme adulte. Cette discipline a beaucoup évolué ces dernières années avec l'essor des nouvelles techniques d’imagerie in vivo, des « omiques » et des techniques de transgénèse. Aux progrès technologiques s’ajoutent les avancées importantes en génétique et épigénétique, tout cela permettant d’avoir aujourd’hui une vision beaucoup plus intégrée des mécanismes fondamentaux de la biologie du développement. L’objectif de l’ouvrage est de fournir une vision synthétique et moderne de la discipline tout en montrant son lien avec la biologie cellulaire, la génétique, la physiologie et la médecine. Les principaux modèles, historiques ou émergents, sont présentés puis les grandes étapes du développement sont détaillées en s’appuyant sur les données les plus récentes. Un chapitre aborde l’importance de l’apport de la biologie du développement dans la compréhension de nombreuses pathologies, dont le cancer. |
Journal Articles |
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| 107. | Baron, Olga Lucia; Deleury, Emeline; Reichhart, Jean-Marc; Coustau, Christine The LBP/BPI multigenic family in invertebrates: Evolutionary history and evidences of specialization in mollusks Journal Article Developmental & Comparative Immunology, 57 , pp. 20–30, 2016, ISSN: 0145305X. @article{baron_lbp/bpi_2016, title = {The LBP/BPI multigenic family in invertebrates: Evolutionary history and evidences of specialization in mollusks}, author = { Olga Lucia Baron and Emeline Deleury and Jean-Marc Reichhart and Christine Coustau}, url = {http://linkinghub.elsevier.com/retrieve/pii/S0145305X15300756}, doi = {10.1016/j.dci.2015.11.006}, issn = {0145305X}, year = {2016}, date = {2016-01-01}, urldate = {2017-07-12}, journal = {Developmental & Comparative Immunology}, volume = {57}, pages = {20--30}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
2015 |
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Journal Articles |
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| 106. | Veillard, Florian; Troxler, Laurent; Reichhart, Jean-Marc Drosophila melanogaster clip-domain serine proteases: Structure, function and regulation Journal Article Biochimie, 122 , pp. 255-269, 2015, ISBN: 0300-9084. @article{veillard_drosophila_2015, title = {Drosophila melanogaster clip-domain serine proteases: Structure, function and regulation}, author = { Florian Veillard and Laurent Troxler and Jean-Marc Reichhart}, url = {http://www.sciencedirect.com/science/article/pii/S030090841500317X}, doi = {10.1016/j.biochi.2015.10.007}, isbn = {0300-9084}, year = {2015}, date = {2015-10-08}, journal = {Biochimie}, volume = {122}, pages = {255-269}, abstract = {Mammalian chymotrypsin-like serine proteases (SPs) are one of the best-studied family of enzymes with roles in a wide range of physiological processes, including digestion, blood coagulation, fibrinolysis and humoral immunity. Extracellular SPs can form cascades, in which one protease activates the zymogen of the next protease in the chain, to amplify physiological or pathological signals. These extracellular SPs are generally multi-domain proteins, with pro-domains that are involved in protein–protein interactions critical for the sequential organization of the cascades, the control of their intensity and their proper localization. Far less is known about invertebrate SPs than their mammalian counterparts. In insect genomes, SPs and their proteolytically inactive homologs (SPHs) constitute large protein families. In addition to the chymotrypsin fold, many of these proteins contain additional structural domains, often with conserved mammalian orthologues. However, the largest group of arthropod SP regulatory modules is the clip domains family, which has only been identified in arthropods. The clip-domain SPs are extracellular and have roles in the immune response and embryonic development. The powerful reverse-genetics tools in Drosophila melanogaster have been essential to identify the functions of clip-SPs and their organization in sequential cascades. This review focuses on the current knowledge of Drosophila clip-SPs and presents, when necessary, data obtained in other insect models. We will first cover the biochemical and structural features of clip domain SPs and SPHs. Clip-SPs are implicated in three main biological processes: the control of the dorso-ventral patterning during embryonic development; the activation of the Toll-mediated response to microbial infections and the prophenoloxydase cascade, which triggers melanization. Finally, we review the regulation of SPs and SPHs, from specificity of activation to inhibition by endogenous or pathogen-encoded inhibitors.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Mammalian chymotrypsin-like serine proteases (SPs) are one of the best-studied family of enzymes with roles in a wide range of physiological processes, including digestion, blood coagulation, fibrinolysis and humoral immunity. Extracellular SPs can form cascades, in which one protease activates the zymogen of the next protease in the chain, to amplify physiological or pathological signals. These extracellular SPs are generally multi-domain proteins, with pro-domains that are involved in protein–protein interactions critical for the sequential organization of the cascades, the control of their intensity and their proper localization. Far less is known about invertebrate SPs than their mammalian counterparts. In insect genomes, SPs and their proteolytically inactive homologs (SPHs) constitute large protein families. In addition to the chymotrypsin fold, many of these proteins contain additional structural domains, often with conserved mammalian orthologues. However, the largest group of arthropod SP regulatory modules is the clip domains family, which has only been identified in arthropods. The clip-domain SPs are extracellular and have roles in the immune response and embryonic development. The powerful reverse-genetics tools in Drosophila melanogaster have been essential to identify the functions of clip-SPs and their organization in sequential cascades. This review focuses on the current knowledge of Drosophila clip-SPs and presents, when necessary, data obtained in other insect models. We will first cover the biochemical and structural features of clip domain SPs and SPHs. Clip-SPs are implicated in three main biological processes: the control of the dorso-ventral patterning during embryonic development; the activation of the Toll-mediated response to microbial infections and the prophenoloxydase cascade, which triggers melanization. Finally, we review the regulation of SPs and SPHs, from specificity of activation to inhibition by endogenous or pathogen-encoded inhibitors. |
| 105. | Chamy, Laure El; Matt, Nicolas; Ntwasa, Monde; Reichhart, Jean-Marc The multilayered innate immune defense of the gut Journal Article Biomed J, 38 (4), pp. 276–284, 2015, ISSN: 2320-2890. @article{el_chamy_multilayered_2015, title = {The multilayered innate immune defense of the gut}, author = { Laure El Chamy and Nicolas Matt and Monde Ntwasa and Jean-Marc Reichhart}, url = {http://www.biomedj.org/text.asp?2015/38/4/276/158621}, doi = {10.4103/2319-4170.158621}, issn = {2320-2890}, year = {2015}, date = {2015-08-01}, journal = {Biomed J}, volume = {38}, number = {4}, pages = {276--284}, abstract = {In the wild, the fruit fly Drosophila melanogaster thrives on rotten fruit. The digestive tract maintains a powerful gut immune barrier to regulate the ingested microbiota, including entomopathogenic bacteria. This gut immune barrier includes a chitinous peritrophic matrix that isolates the gut contents from the epithelial cells. In addition, the epithelial cells are tightly sealed by septate junctions and can mount an inducible immune response. This local response can be activated by invasive bacteria, or triggered by commensal bacteria in the gut lumen. As with chronic inflammation in mammals, constitutive activation of the gut innate immune response is detrimental to the health of flies. Accordingly, the Drosophila gut innate immune response is tightly regulated to maintain the endogenous microbiota, while preventing infections by pathogenic microorganisms.}, keywords = {}, pubstate = {published}, tppubtype = {article} } In the wild, the fruit fly Drosophila melanogaster thrives on rotten fruit. The digestive tract maintains a powerful gut immune barrier to regulate the ingested microbiota, including entomopathogenic bacteria. This gut immune barrier includes a chitinous peritrophic matrix that isolates the gut contents from the epithelial cells. In addition, the epithelial cells are tightly sealed by septate junctions and can mount an inducible immune response. This local response can be activated by invasive bacteria, or triggered by commensal bacteria in the gut lumen. As with chronic inflammation in mammals, constitutive activation of the gut innate immune response is detrimental to the health of flies. Accordingly, the Drosophila gut innate immune response is tightly regulated to maintain the endogenous microbiota, while preventing infections by pathogenic microorganisms. |
2014 |
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Journal Articles |
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| 104. | Bonnay, François; Nguyen, Xuan-Hung; Cohen-Berros, Eva; Troxler, Laurent; Batsche, Eric; Camonis, Jacques; Takeuchi, Osamu; Reichhart, Jean-Marc; Matt, Nicolas Akirin specifies NF-κB selectivity of Drosophila innate immune response via chromatin remodeling Journal Article EMBO J., 33 (20), pp. 2349–2362, 2014, ISSN: 1460-2075. @article{bonnay_akirin_2014, title = {Akirin specifies NF-κB selectivity of Drosophila innate immune response via chromatin remodeling}, author = { François Bonnay and Xuan-Hung Nguyen and Eva Cohen-Berros and Laurent Troxler and Eric Batsche and Jacques Camonis and Osamu Takeuchi and Jean-Marc Reichhart and Nicolas Matt}, doi = {10.15252/embj.201488456}, issn = {1460-2075}, year = {2014}, date = {2014-10-01}, journal = {EMBO J.}, volume = {33}, number = {20}, pages = {2349--2362}, abstract = {The network of NF-κB-dependent transcription that activates both pro- and anti-inflammatory genes in mammals is still unclear. As NF-κB factors are evolutionarily conserved, we used Drosophila to understand this network. The NF-κB transcription factor Relish activates effector gene expression following Gram-negative bacterial immune challenge. Here, we show, using a genome-wide approach, that the conserved nuclear protein Akirin is a NF-κB co-factor required for the activation of a subset of Relish-dependent genes correlating with the presence of H3K4ac epigenetic marks. A large-scale unbiased proteomic analysis revealed that Akirin orchestrates NF-κB transcriptional selectivity through the recruitment of the Osa-containing-SWI/SNF-like Brahma complex (BAP). Immune challenge in Drosophila shows that Akirin is required for the transcription of a subset of effector genes, but dispensable for the transcription of genes that are negative regulators of the innate immune response. Therefore, Akirins act as molecular selectors specifying the choice between subsets of NF-κB target genes. The discovery of this mechanism, conserved in mammals, paves the way for the establishment of more specific and less toxic anti-inflammatory drugs targeting pro-inflammatory genes.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The network of NF-κB-dependent transcription that activates both pro- and anti-inflammatory genes in mammals is still unclear. As NF-κB factors are evolutionarily conserved, we used Drosophila to understand this network. The NF-κB transcription factor Relish activates effector gene expression following Gram-negative bacterial immune challenge. Here, we show, using a genome-wide approach, that the conserved nuclear protein Akirin is a NF-κB co-factor required for the activation of a subset of Relish-dependent genes correlating with the presence of H3K4ac epigenetic marks. A large-scale unbiased proteomic analysis revealed that Akirin orchestrates NF-κB transcriptional selectivity through the recruitment of the Osa-containing-SWI/SNF-like Brahma complex (BAP). Immune challenge in Drosophila shows that Akirin is required for the transcription of a subset of effector genes, but dispensable for the transcription of genes that are negative regulators of the innate immune response. Therefore, Akirins act as molecular selectors specifying the choice between subsets of NF-κB target genes. The discovery of this mechanism, conserved in mammals, paves the way for the establishment of more specific and less toxic anti-inflammatory drugs targeting pro-inflammatory genes. |
| 103. | Tartey, Sarang; Matsushita, Kazufumi ; Vandenbon, Alexis ; Ori, Daisuke ; Imamura, Tomoko ; Mino, Takashi ; Standley, Daron M; Hoffmann, Jules A; Reichhart, Jean-Marc ; Akira, Shizuo ; Takeuchi, Osamu Akirin2 is critical for inducing inflammatory genes by bridging IκB-ζ and the SWI/SNF complex Journal Article EMBO J., 33 (20), pp. 2332–2348, 2014, ISSN: 1460-2075. @article{tartey_akirin2_2014, title = {Akirin2 is critical for inducing inflammatory genes by bridging IκB-ζ and the SWI/SNF complex}, author = { Sarang Tartey and Kazufumi Matsushita and Alexis Vandenbon and Daisuke Ori and Tomoko Imamura and Takashi Mino and Daron M. Standley and Jules A. Hoffmann and Jean-Marc Reichhart and Shizuo Akira and Osamu Takeuchi}, doi = {10.15252/embj.201488447}, issn = {1460-2075}, year = {2014}, date = {2014-10-01}, journal = {EMBO J.}, volume = {33}, number = {20}, pages = {2332--2348}, abstract = {Transcription of inflammatory genes in innate immune cells is coordinately regulated by transcription factors, including NF-κB, and chromatin modifiers. However, it remains unclear how microbial sensing initiates chromatin remodeling. Here, we show that Akirin2, an evolutionarily conserved nuclear protein, bridges NF-κB and the chromatin remodeling SWI/SNF complex by interacting with BRG1-Associated Factor 60 (BAF60) proteins as well as IκB-ζ, which forms a complex with the NF-κB p50 subunit. These interactions are essential for Toll-like receptor-, RIG-I-, and Listeria-mediated expression of proinflammatory genes including Il6 and Il12b in macrophages. Consistently, effective clearance of Listeria infection required Akirin2. Furthermore, Akirin2 and IκB-ζ recruitment to the Il6 promoter depend upon the presence of IκB-ζ and Akirin2, respectively, for regulation of chromatin remodeling. BAF60 proteins were also essential for the induction of Il6 in response to LPS stimulation. Collectively, the IκB-ζ-Akirin2-BAF60 complex physically links the NF-κB and SWI/SNF complexes in innate immune cell activation. By recruiting SWI/SNF chromatin remodellers to IκB-ζ, transcriptional coactivator for NF-κB, the conserved nuclear protein Akirin2 stimulates pro-inflammatory gene promoters in mouse macrophages during innate immune responses to viral or bacterial infection.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Transcription of inflammatory genes in innate immune cells is coordinately regulated by transcription factors, including NF-κB, and chromatin modifiers. However, it remains unclear how microbial sensing initiates chromatin remodeling. Here, we show that Akirin2, an evolutionarily conserved nuclear protein, bridges NF-κB and the chromatin remodeling SWI/SNF complex by interacting with BRG1-Associated Factor 60 (BAF60) proteins as well as IκB-ζ, which forms a complex with the NF-κB p50 subunit. These interactions are essential for Toll-like receptor-, RIG-I-, and Listeria-mediated expression of proinflammatory genes including Il6 and Il12b in macrophages. Consistently, effective clearance of Listeria infection required Akirin2. Furthermore, Akirin2 and IκB-ζ recruitment to the Il6 promoter depend upon the presence of IκB-ζ and Akirin2, respectively, for regulation of chromatin remodeling. BAF60 proteins were also essential for the induction of Il6 in response to LPS stimulation. Collectively, the IκB-ζ-Akirin2-BAF60 complex physically links the NF-κB and SWI/SNF complexes in innate immune cell activation. By recruiting SWI/SNF chromatin remodellers to IκB-ζ, transcriptional coactivator for NF-κB, the conserved nuclear protein Akirin2 stimulates pro-inflammatory gene promoters in mouse macrophages during innate immune responses to viral or bacterial infection. |
| 102. | Leclerc, Vincent; Chamy, Laure El; Ntwasa, Monde; Reichhart, Jean-Marc Drosophila melanogaster model in innate immunity. Journal Article Trends in Entomology, 10 , pp. 73–86, 2014. @article{leclerc_drosophila_2014, title = {Drosophila melanogaster model in innate immunity.}, author = { Vincent Leclerc and Laure El Chamy and Monde Ntwasa and Jean-Marc Reichhart}, year = {2014}, date = {2014-01-01}, journal = {Trends in Entomology}, volume = {10}, pages = {73--86}, abstract = {Due relative simplicity of the fly and availability of large amounts of genetic tools, Drosophila melanogaster has proven to be an excellent model to study the basic principles of innate immunity. This is illustrated by the discovery of the Toll-like receptor functions in pathogen sensing, recognised by the 2011 Nobel Prize in Physiology and Medicine awarded to Jules Hoffmann. Drosophila can also be used as an in vivo, genetically tractable model, to analyse various aspects of host-pathogen interactions including virulence factor mechanisms of action.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Due relative simplicity of the fly and availability of large amounts of genetic tools, Drosophila melanogaster has proven to be an excellent model to study the basic principles of innate immunity. This is illustrated by the discovery of the Toll-like receptor functions in pathogen sensing, recognised by the 2011 Nobel Prize in Physiology and Medicine awarded to Jules Hoffmann. Drosophila can also be used as an in vivo, genetically tractable model, to analyse various aspects of host-pathogen interactions including virulence factor mechanisms of action. |
2013 |
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Journal Articles |
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| 101. | Kobayashi, Taira; Ogawa, Michinaga; Sanada, Takahito; Mimuro, Hitomi; Kim, Minsoo; Ashida, Hiroshi; Akakura, Reiko; Yoshida, Mitsutaka; Kawalec, Magdalena; Reichhart, Jean-Marc; Mizushima, Tsunehiro; Sasakawa, Chihiro The Shigella OspC3 effector inhibits caspase-4, antagonizes inflammatory cell death, and promotes epithelial infection Journal Article Cell Host Microbe, 13 (5), pp. 570–583, 2013, ISSN: 1934-6069. @article{kobayashi_shigella_2013, title = {The Shigella OspC3 effector inhibits caspase-4, antagonizes inflammatory cell death, and promotes epithelial infection}, author = { Taira Kobayashi and Michinaga Ogawa and Takahito Sanada and Hitomi Mimuro and Minsoo Kim and Hiroshi Ashida and Reiko Akakura and Mitsutaka Yoshida and Magdalena Kawalec and Jean-Marc Reichhart and Tsunehiro Mizushima and Chihiro Sasakawa}, doi = {10.1016/j.chom.2013.04.012}, issn = {1934-6069}, year = {2013}, date = {2013-05-01}, journal = {Cell Host Microbe}, volume = {13}, number = {5}, pages = {570--583}, abstract = {Caspase-mediated inflammatory cell death acts as an intrinsic defense mechanism against infection. Bacterial pathogens deploy countermeasures against inflammatory cell death, but the mechanisms by which they do this remain largely unclear. In a screen for Shigella flexneri effectors that regulate cell death during infection, we discovered that Shigella infection induced acute inflammatory, caspase-4-dependent epithelial cell death, which is counteracted by the bacterial OspC3 effector. OspC3 interacts with the caspase-4-p19 subunit and inhibits its activation by preventing caspase-4-p19 and caspase-4-p10 heterodimerization by depositing the conserved OspC3 X1-Y-X₂-D-X₃ motif at the putative catalytic pocket of caspase-4. Infection of guinea pigs with a Shigella ospC3-deficient mutant resulted in enhanced inflammatory cell death and associated symptoms, correlating with decreased bacterial burdens. Salmonella Typhimurium and enteropathogenic Escherichia coli infection also induced caspase-4-dependent epithelial death. These findings highlight the importance of caspase-4-dependent innate immune responses and demonstrate that Shigella delivers a caspase-4-specific inhibitor to delay epithelial cell death and promote infection.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Caspase-mediated inflammatory cell death acts as an intrinsic defense mechanism against infection. Bacterial pathogens deploy countermeasures against inflammatory cell death, but the mechanisms by which they do this remain largely unclear. In a screen for Shigella flexneri effectors that regulate cell death during infection, we discovered that Shigella infection induced acute inflammatory, caspase-4-dependent epithelial cell death, which is counteracted by the bacterial OspC3 effector. OspC3 interacts with the caspase-4-p19 subunit and inhibits its activation by preventing caspase-4-p19 and caspase-4-p10 heterodimerization by depositing the conserved OspC3 X1-Y-X₂-D-X₃ motif at the putative catalytic pocket of caspase-4. Infection of guinea pigs with a Shigella ospC3-deficient mutant resulted in enhanced inflammatory cell death and associated symptoms, correlating with decreased bacterial burdens. Salmonella Typhimurium and enteropathogenic Escherichia coli infection also induced caspase-4-dependent epithelial death. These findings highlight the importance of caspase-4-dependent innate immune responses and demonstrate that Shigella delivers a caspase-4-specific inhibitor to delay epithelial cell death and promote infection. |
| 100. | Bonnay, François; Cohen-Berros, Eva ; Hoffmann, Martine ; Kim, Sabrina Y; Boulianne, Gabrielle L; Hoffmann, Jules A; Matt, Nicolas ; Reichhart, Jean-Marc Big bang gene modulates gut immune tolerance in Drosophila Journal Article Proc. Natl. Acad. Sci. U.S.A., 110 (8), pp. 2957–2962, 2013, ISSN: 1091-6490. @article{bonnay_big_2013, title = {Big bang gene modulates gut immune tolerance in Drosophila}, author = { François Bonnay and Eva Cohen-Berros and Martine Hoffmann and Sabrina Y. Kim and Gabrielle L. Boulianne and Jules A. Hoffmann and Nicolas Matt and Jean-Marc Reichhart}, doi = {10.1073/pnas.1221910110}, issn = {1091-6490}, year = {2013}, date = {2013-02-01}, journal = {Proc. Natl. Acad. Sci. U.S.A.}, volume = {110}, number = {8}, pages = {2957--2962}, abstract = {Chronic inflammation of the intestine is detrimental to mammals. Similarly, constant activation of the immune response in the gut by the endogenous flora is suspected to be harmful to Drosophila. Therefore, the innate immune response in the gut of Drosophila melanogaster is tightly balanced to simultaneously prevent infections by pathogenic microorganisms and tolerate the endogenous flora. Here we describe the role of the big bang (bbg) gene, encoding multiple membrane-associated PDZ (PSD-95, Discs-large, ZO-1) domain-containing protein isoforms, in the modulation of the gut immune response. We show that in the adult Drosophila midgut, BBG is present at the level of the septate junctions, on the apical side of the enterocytes. In the absence of BBG, these junctions become loose, enabling the intestinal flora to trigger a constitutive activation of the anterior midgut immune response. This chronic epithelial inflammation leads to a reduced lifespan of bbg mutant flies. Clearing the commensal flora by antibiotics prevents the abnormal activation of the gut immune response and restores a normal lifespan. We now provide genetic evidence that Drosophila septate junctions are part of the gut immune barrier, a function that is evolutionarily conserved in mammals. Collectively, our data suggest that septate junctions are required to maintain the subtle balance between immune tolerance and immune response in the Drosophila gut, which represents a powerful model to study inflammatory bowel diseases.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Chronic inflammation of the intestine is detrimental to mammals. Similarly, constant activation of the immune response in the gut by the endogenous flora is suspected to be harmful to Drosophila. Therefore, the innate immune response in the gut of Drosophila melanogaster is tightly balanced to simultaneously prevent infections by pathogenic microorganisms and tolerate the endogenous flora. Here we describe the role of the big bang (bbg) gene, encoding multiple membrane-associated PDZ (PSD-95, Discs-large, ZO-1) domain-containing protein isoforms, in the modulation of the gut immune response. We show that in the adult Drosophila midgut, BBG is present at the level of the septate junctions, on the apical side of the enterocytes. In the absence of BBG, these junctions become loose, enabling the intestinal flora to trigger a constitutive activation of the anterior midgut immune response. This chronic epithelial inflammation leads to a reduced lifespan of bbg mutant flies. Clearing the commensal flora by antibiotics prevents the abnormal activation of the gut immune response and restores a normal lifespan. We now provide genetic evidence that Drosophila septate junctions are part of the gut immune barrier, a function that is evolutionarily conserved in mammals. Collectively, our data suggest that septate junctions are required to maintain the subtle balance between immune tolerance and immune response in the Drosophila gut, which represents a powerful model to study inflammatory bowel diseases. |
| 99. | Baron, Olga Lucia; van West, Pieter; Industri, Benoit; Ponchet, Michel; Dubreuil, Géraldine; Gourbal, Benjamin; Reichhart, Jean-Marc; Coustau, Christine Parental transfer of the antimicrobial protein LBP/BPI protects Biomphalaria glabrata eggs against oomycete infections Journal Article PLoS Pathog., 9 (12), pp. e1003792, 2013, ISSN: 1553-7374. @article{baron_parental_2013, title = {Parental transfer of the antimicrobial protein LBP/BPI protects Biomphalaria glabrata eggs against oomycete infections}, author = { Olga Lucia Baron and Pieter van West and Benoit Industri and Michel Ponchet and Géraldine Dubreuil and Benjamin Gourbal and Jean-Marc Reichhart and Christine Coustau}, doi = {10.1371/journal.ppat.1003792}, issn = {1553-7374}, year = {2013}, date = {2013-01-01}, journal = {PLoS Pathog.}, volume = {9}, number = {12}, pages = {e1003792}, abstract = {Vertebrate females transfer antibodies via the placenta, colostrum and milk or via the egg yolk to protect their immunologically immature offspring against pathogens. This evolutionarily important transfer of immunity is poorly documented in invertebrates and basic questions remain regarding the nature and extent of parental protection of offspring. In this study, we show that a lipopolysaccharide binding protein/bactericidal permeability increasing protein family member from the invertebrate Biomphalaria glabrata (BgLBP/BPI1) is massively loaded into the eggs of this freshwater snail. Native and recombinant proteins displayed conserved LPS-binding, antibacterial and membrane permeabilizing activities. A broad screening of various pathogens revealed a previously unknown biocidal activity of the protein against pathogenic water molds (oomycetes), which is conserved in human BPI. RNAi-dependent silencing of LBP/BPI in the parent snails resulted in a significant reduction of reproductive success and extensive death of eggs through oomycete infections. This work provides the first functional evidence that a LBP/BPI is involved in the parental immune protection of invertebrate offspring and reveals a novel and conserved biocidal activity for LBP/BPI family members.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Vertebrate females transfer antibodies via the placenta, colostrum and milk or via the egg yolk to protect their immunologically immature offspring against pathogens. This evolutionarily important transfer of immunity is poorly documented in invertebrates and basic questions remain regarding the nature and extent of parental protection of offspring. In this study, we show that a lipopolysaccharide binding protein/bactericidal permeability increasing protein family member from the invertebrate Biomphalaria glabrata (BgLBP/BPI1) is massively loaded into the eggs of this freshwater snail. Native and recombinant proteins displayed conserved LPS-binding, antibacterial and membrane permeabilizing activities. A broad screening of various pathogens revealed a previously unknown biocidal activity of the protein against pathogenic water molds (oomycetes), which is conserved in human BPI. RNAi-dependent silencing of LBP/BPI in the parent snails resulted in a significant reduction of reproductive success and extensive death of eggs through oomycete infections. This work provides the first functional evidence that a LBP/BPI is involved in the parental immune protection of invertebrate offspring and reveals a novel and conserved biocidal activity for LBP/BPI family members. |
2012 |
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Journal Articles |
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| 98. | Lemaitre, Bruno; Nicolas, Emmanuelle ; Michaut, Lydia ; Reichhart, Jean-Marc ; Hoffmann, Jules A Pillars article: the dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell. 1996. 86: 973-983 Journal Article J. Immunol., 188 (11), pp. 5210–5220, 2012, ISSN: 1550-6606. @article{lemaitre_pillars_2012, title = {Pillars article: the dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell. 1996. 86: 973-983}, author = { Bruno Lemaitre and Emmanuelle Nicolas and Lydia Michaut and Jean-Marc Reichhart and Jules A. Hoffmann}, issn = {1550-6606}, year = {2012}, date = {2012-06-01}, journal = {J. Immunol.}, volume = {188}, number = {11}, pages = {5210--5220}, abstract = {The cytokine-induced activation cascade of NF-kappaB in mammals and the activation of the morphogen dorsal in Drosophila embryos show striking structural and functional similarities (Toll/IL-1, Cactus/I-kappaB, and dorsal/NF-kappaB). Here we demonstrate that these parallels extend to the immune response of Drosophila. In particular, the intracellular components of the dorsoventral signaling pathway (except for dorsal) and the extracellular Toll ligand, spätzle regulatory gene cassette, control expression of the antifungal peptide gene drosomycin in adults. We also show that mutations in the Toll signaling pathway dramatically reduce survival after fungal infection. Antibacterial genes are induced either by a distinct pathway involving the immune deficiency gene (imd) or by combined activation of both imd and dorsoventral pathways.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The cytokine-induced activation cascade of NF-kappaB in mammals and the activation of the morphogen dorsal in Drosophila embryos show striking structural and functional similarities (Toll/IL-1, Cactus/I-kappaB, and dorsal/NF-kappaB). Here we demonstrate that these parallels extend to the immune response of Drosophila. In particular, the intracellular components of the dorsoventral signaling pathway (except for dorsal) and the extracellular Toll ligand, spätzle regulatory gene cassette, control expression of the antifungal peptide gene drosomycin in adults. We also show that mutations in the Toll signaling pathway dramatically reduce survival after fungal infection. Antibacterial genes are induced either by a distinct pathway involving the immune deficiency gene (imd) or by combined activation of both imd and dorsoventral pathways. |
| 97. | Ezekowitz, Alan R B; Dimarcq, Jean-Luc; Kafatos, Fotis; Levashina, Elena A; Ferrandon, Dominique; Hetru, Charles; Imler, Jean-Luc; Reichhart, Jean-Marc Lawrence's book review unfair to Hoffmann Journal Article Curr. Biol., 22 (12), pp. R482, 2012, ISSN: 1879-0445. @article{ezekowitz_lawrences_2012, title = {Lawrence's book review unfair to Hoffmann}, author = {R. Alan B. Ezekowitz and Jean-Luc Dimarcq and Fotis Kafatos and Elena A. Levashina and Dominique Ferrandon and Charles Hetru and Jean-Luc Imler and Jean-Marc Reichhart}, doi = {10.1016/j.cub.2012.05.015}, issn = {1879-0445}, year = {2012}, date = {2012-06-01}, journal = {Curr. Biol.}, volume = {22}, number = {12}, pages = {R482}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
| 96. | Deleury, Emeline; Dubreuil, Géraldine; Elangovan, Namasivayam; Wajnberg, Eric; Reichhart, Jean-Marc; Gourbal, Benjamin; Duval, David; Baron, Olga Lucia; Gouzy, Jérôme; Coustau, Christine Specific versus non-specific immune responses in an invertebrate species evidenced by a comparative de novo sequencing study Journal Article PLoS ONE, 7 (3), pp. e32512, 2012, ISSN: 1932-6203. @article{deleury_specific_2012, title = {Specific versus non-specific immune responses in an invertebrate species evidenced by a comparative de novo sequencing study}, author = { Emeline Deleury and Géraldine Dubreuil and Namasivayam Elangovan and Eric Wajnberg and Jean-Marc Reichhart and Benjamin Gourbal and David Duval and Olga Lucia Baron and Jérôme Gouzy and Christine Coustau}, doi = {10.1371/journal.pone.0032512}, issn = {1932-6203}, year = {2012}, date = {2012-01-01}, journal = {PLoS ONE}, volume = {7}, number = {3}, pages = {e32512}, abstract = {Our present understanding of the functioning and evolutionary history of invertebrate innate immunity derives mostly from studies on a few model species belonging to ecdysozoa. In particular, the characterization of signaling pathways dedicated to specific responses towards fungi and Gram-positive or Gram-negative bacteria in Drosophila melanogaster challenged our original view of a non-specific immunity in invertebrates. However, much remains to be elucidated from lophotrochozoan species. To investigate the global specificity of the immune response in the fresh-water snail Biomphalaria glabrata, we used massive Illumina sequencing of 5'-end cDNAs to compare expression profiles after challenge by Gram-positive or Gram-negative bacteria or after a yeast challenge. 5'-end cDNA sequencing of the libraries yielded over 12 millions high quality reads. To link these short reads to expressed genes, we prepared a reference transcriptomic database through automatic assembly and annotation of the 758,510 redundant sequences (ESTs, mRNAs) of B. glabrata available in public databases. Computational analysis of Illumina reads followed by multivariate analyses allowed identification of 1685 candidate transcripts differentially expressed after an immune challenge, with a two fold ratio between transcripts showing a challenge-specific expression versus a lower or non-specific differential expression. Differential expression has been validated using quantitative PCR for a subset of randomly selected candidates. Predicted functions of annotated candidates (approx. 700 unisequences) belonged to a large extend to similar functional categories or protein types. This work significantly expands upon previous gene discovery and expression studies on B. glabrata and suggests that responses to various pathogens may involve similar immune processes or signaling pathways but different genes belonging to multigenic families. These results raise the question of the importance of gene duplication and acquisition of paralog functional diversity in the evolution of specific invertebrate immune responses.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Our present understanding of the functioning and evolutionary history of invertebrate innate immunity derives mostly from studies on a few model species belonging to ecdysozoa. In particular, the characterization of signaling pathways dedicated to specific responses towards fungi and Gram-positive or Gram-negative bacteria in Drosophila melanogaster challenged our original view of a non-specific immunity in invertebrates. However, much remains to be elucidated from lophotrochozoan species. To investigate the global specificity of the immune response in the fresh-water snail Biomphalaria glabrata, we used massive Illumina sequencing of 5'-end cDNAs to compare expression profiles after challenge by Gram-positive or Gram-negative bacteria or after a yeast challenge. 5'-end cDNA sequencing of the libraries yielded over 12 millions high quality reads. To link these short reads to expressed genes, we prepared a reference transcriptomic database through automatic assembly and annotation of the 758,510 redundant sequences (ESTs, mRNAs) of B. glabrata available in public databases. Computational analysis of Illumina reads followed by multivariate analyses allowed identification of 1685 candidate transcripts differentially expressed after an immune challenge, with a two fold ratio between transcripts showing a challenge-specific expression versus a lower or non-specific differential expression. Differential expression has been validated using quantitative PCR for a subset of randomly selected candidates. Predicted functions of annotated candidates (approx. 700 unisequences) belonged to a large extend to similar functional categories or protein types. This work significantly expands upon previous gene discovery and expression studies on B. glabrata and suggests that responses to various pathogens may involve similar immune processes or signaling pathways but different genes belonging to multigenic families. These results raise the question of the importance of gene duplication and acquisition of paralog functional diversity in the evolution of specific invertebrate immune responses. |
2011 |
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Journal Articles |
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| 95. | Boyer, Laurent; Magoc, Lorin; Dejardin, Stephanie; Cappillino, Michael; Paquette, Nicholas; Hinault, Charlotte; Charriere, Guillaume M; Ip, Eddie W K; Fracchia, Shannon; Hennessy, Elizabeth; Erturk-Hasdemir, Deniz; Reichhart, Jean-Marc; Silverman, Neal; Lacy-Hulbert, Adam; Stuart, Lynda M Pathogen-derived effectors trigger protective immunity via activation of the Rac2 enzyme and the IMD or Rip kinase signaling pathway Journal Article Immunity, 35 (4), pp. 536–549, 2011, ISSN: 1097-4180. @article{boyer_pathogen-derived_2011, title = {Pathogen-derived effectors trigger protective immunity via activation of the Rac2 enzyme and the IMD or Rip kinase signaling pathway}, author = { Laurent Boyer and Lorin Magoc and Stephanie Dejardin and Michael Cappillino and Nicholas Paquette and Charlotte Hinault and Guillaume M. Charriere and W. K. Eddie Ip and Shannon Fracchia and Elizabeth Hennessy and Deniz Erturk-Hasdemir and Jean-Marc Reichhart and Neal Silverman and Adam Lacy-Hulbert and Lynda M. Stuart}, doi = {10.1016/j.immuni.2011.08.015}, issn = {1097-4180}, year = {2011}, date = {2011-10-01}, journal = {Immunity}, volume = {35}, number = {4}, pages = {536--549}, abstract = {Although infections with virulent pathogens often induce a strong inflammatory reaction, what drives the increased immune response to pathogens compared to nonpathogenic microbes is poorly understood. One possibility is that the immune system senses the level of threat from a microorganism and augments the response accordingly. Here, focusing on cytotoxic necrotizing factor 1 (CNF1), an Escherichia coli-derived effector molecule, we showed the host indirectly sensed the pathogen by monitoring for the effector that modified RhoGTPases. CNF1 modified Rac2, which then interacted with the innate immune adaptors IMD and Rip1-Rip2 in flies and mammalian cells, respectively, to drive an immune response. This response was protective and increased the ability of the host to restrict pathogen growth, thus defining a mechanism of effector-triggered immunity that contributes to how metazoans defend against microbes with pathogenic potential.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Although infections with virulent pathogens often induce a strong inflammatory reaction, what drives the increased immune response to pathogens compared to nonpathogenic microbes is poorly understood. One possibility is that the immune system senses the level of threat from a microorganism and augments the response accordingly. Here, focusing on cytotoxic necrotizing factor 1 (CNF1), an Escherichia coli-derived effector molecule, we showed the host indirectly sensed the pathogen by monitoring for the effector that modified RhoGTPases. CNF1 modified Rac2, which then interacted with the innate immune adaptors IMD and Rip1-Rip2 in flies and mammalian cells, respectively, to drive an immune response. This response was protective and increased the ability of the host to restrict pathogen growth, thus defining a mechanism of effector-triggered immunity that contributes to how metazoans defend against microbes with pathogenic potential. |
| 94. | Ogawa, Michinaga; Yoshikawa, Yuko; Kobayashi, Taira; Mimuro, Hitomi; Fukumatsu, Makoto; Kiga, Kotaro; Piao, Zhenzi; Ashida, Hiroshi; Yoshida, Mitsutaka; Kakuta, Shigeru; Koyama, Tomohiro; Goto, Yoshiyuki; Nagatake, Takahiro; Nagai, Shinya; Kiyono, Hiroshi; Kawalec, Magdalena; Reichhart, Jean-Marc; Sasakawa, Chihiro A Tecpr1-dependent selective autophagy pathway targets bacterial pathogens Journal Article Cell Host Microbe, 9 (5), pp. 376–389, 2011, ISSN: 1934-6069. @article{ogawa_tecpr1-dependent_2011, title = {A Tecpr1-dependent selective autophagy pathway targets bacterial pathogens}, author = { Michinaga Ogawa and Yuko Yoshikawa and Taira Kobayashi and Hitomi Mimuro and Makoto Fukumatsu and Kotaro Kiga and Zhenzi Piao and Hiroshi Ashida and Mitsutaka Yoshida and Shigeru Kakuta and Tomohiro Koyama and Yoshiyuki Goto and Takahiro Nagatake and Shinya Nagai and Hiroshi Kiyono and Magdalena Kawalec and Jean-Marc Reichhart and Chihiro Sasakawa}, doi = {10.1016/j.chom.2011.04.010}, issn = {1934-6069}, year = {2011}, date = {2011-05-01}, journal = {Cell Host Microbe}, volume = {9}, number = {5}, pages = {376--389}, abstract = {Selective autophagy of bacterial pathogens represents a host innate immune mechanism. Selective autophagy has been characterized on the basis of distinct cargo receptors but the mechanisms by which different cargo receptors are targeted for autophagic degradation remain unclear. In this study we identified a highly conserved Tectonin domain-containing protein, Tecpr1, as an Atg5 binding partner that colocalized with Atg5 at Shigella-containing phagophores. Tecpr1 activity is necessary for efficient autophagic targeting of bacteria, but has no effect on rapamycin- or starvation-induced canonical autophagy. Tecpr1 interacts with WIPI-2, a yeast Atg18 homolog and PI(3)P-interacting protein required for phagophore formation, and they colocalize to phagophores. Although Tecpr1-deficient mice appear normal, Tecpr1-deficient MEFs were defective for selective autophagy and supported increased intracellular multiplication of Shigella. Further, depolarized mitochondria and misfolded protein aggregates accumulated in the Tecpr1-knockout MEFs. Thus, we identify a Tecpr1-dependent pathway as important in targeting bacterial pathogens for selective autophagy.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Selective autophagy of bacterial pathogens represents a host innate immune mechanism. Selective autophagy has been characterized on the basis of distinct cargo receptors but the mechanisms by which different cargo receptors are targeted for autophagic degradation remain unclear. In this study we identified a highly conserved Tectonin domain-containing protein, Tecpr1, as an Atg5 binding partner that colocalized with Atg5 at Shigella-containing phagophores. Tecpr1 activity is necessary for efficient autophagic targeting of bacteria, but has no effect on rapamycin- or starvation-induced canonical autophagy. Tecpr1 interacts with WIPI-2, a yeast Atg18 homolog and PI(3)P-interacting protein required for phagophore formation, and they colocalize to phagophores. Although Tecpr1-deficient mice appear normal, Tecpr1-deficient MEFs were defective for selective autophagy and supported increased intracellular multiplication of Shigella. Further, depolarized mitochondria and misfolded protein aggregates accumulated in the Tecpr1-knockout MEFs. Thus, we identify a Tecpr1-dependent pathway as important in targeting bacterial pathogens for selective autophagy. |
| 93. | Kellenberger, Christine; Leone, Philippe; Coquet, Laurent; Jouenne, Thierry; Reichhart, Jean-Marc; Roussel, Alain Structure-function analysis of grass clip serine protease involved in Drosophila Toll pathway activation Journal Article J. Biol. Chem., 286 (14), pp. 12300–12307, 2011, ISSN: 1083-351X. @article{kellenberger_structure-function_2011, title = {Structure-function analysis of grass clip serine protease involved in Drosophila Toll pathway activation}, author = { Christine Kellenberger and Philippe Leone and Laurent Coquet and Thierry Jouenne and Jean-Marc Reichhart and Alain Roussel}, doi = {10.1074/jbc.M110.182741}, issn = {1083-351X}, year = {2011}, date = {2011-04-01}, journal = {J. Biol. Chem.}, volume = {286}, number = {14}, pages = {12300--12307}, abstract = {Grass is a clip domain serine protease (SP) involved in a proteolytic cascade triggering the Toll pathway activation of Drosophila during an immune response. Epistasic studies position it downstream of the apical protease ModSP and upstream of the terminal protease Spaetzle-processing enzyme. Here, we report the crystal structure of Grass zymogen. We found that Grass displays a rather deep active site cleft comparable with that of proteases of coagulation and complement cascades. A key distinctive feature is the presence of an additional loop (75-loop) in the proximity of the activation site localized on a protruding loop. All biochemical attempts to hydrolyze the activation site of Grass failed, strongly suggesting restricted access to this region. The 75-loop is thus proposed to constitute an original mechanism to prevent spontaneous activation. A comparison of Grass with clip serine proteases of known function involved in analogous proteolytic cascades allowed us to define two groups, according to the presence of the 75-loop and the conformation of the clip domain. One group (devoid of the 75-loop) contains penultimate proteases whereas the other contains terminal proteases. Using this classification, Grass appears to be a terminal protease. This result is evaluated according to the genetic data documenting Grass function.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Grass is a clip domain serine protease (SP) involved in a proteolytic cascade triggering the Toll pathway activation of Drosophila during an immune response. Epistasic studies position it downstream of the apical protease ModSP and upstream of the terminal protease Spaetzle-processing enzyme. Here, we report the crystal structure of Grass zymogen. We found that Grass displays a rather deep active site cleft comparable with that of proteases of coagulation and complement cascades. A key distinctive feature is the presence of an additional loop (75-loop) in the proximity of the activation site localized on a protruding loop. All biochemical attempts to hydrolyze the activation site of Grass failed, strongly suggesting restricted access to this region. The 75-loop is thus proposed to constitute an original mechanism to prevent spontaneous activation. A comparison of Grass with clip serine proteases of known function involved in analogous proteolytic cascades allowed us to define two groups, according to the presence of the 75-loop and the conformation of the clip domain. One group (devoid of the 75-loop) contains penultimate proteases whereas the other contains terminal proteases. Using this classification, Grass appears to be a terminal protease. This result is evaluated according to the genetic data documenting Grass function. |
| 92. | Aoun, Richard Bou; Hetru, Charles; Troxler, Laurent; Doucet, Daniel; Ferrandon, Dominique; Matt, Nicolas Analysis of thioester-containing proteins during the innate immune response of Drosophila melanogaster Journal Article J Innate Immun, 3 (1), pp. 52–64, 2011, ISSN: 1662-8128. @article{bou_aoun_analysis_2011, title = {Analysis of thioester-containing proteins during the innate immune response of Drosophila melanogaster}, author = { Richard Bou Aoun and Charles Hetru and Laurent Troxler and Daniel Doucet and Dominique Ferrandon and Nicolas Matt}, doi = {10.1159/000321554}, issn = {1662-8128}, year = {2011}, date = {2011-01-01}, journal = {J Innate Immun}, volume = {3}, number = {1}, pages = {52--64}, abstract = {Thioester-containing proteins (TEPs) are conserved proteins among insects that are thought to be involved in innate immunity. In Drosophila, the Tep family is composed of 6 genes named Tep1-Tep6. In this study, we investigated the phylogeny, expression pattern and roles of these genes in the host defense of Drosophila. Protostomian Tep genes are clustered in 3 distinct branches, 1 of which is specific to mosquitoes. Most D. melanogaster Tep genes are expressed in hemocytes, can be induced in the fat body, and are expressed in specific regions of the hypodermis. This expression pattern is consistent with a role in innate immunity. However, we find that TEP1, TEP2, and TEP4 are not strictly required in the body cavity to fight several bacterial and fungal infections. One possibility is that Drosophila TEPs act redundantly or that their absence can be compensated by other components of the immune response. TEPs may thus provide a subtle selective advantage during evolution. Alternatively, they may be required in host defense against specific as yet unidentified natural pathogens of Drosophila.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Thioester-containing proteins (TEPs) are conserved proteins among insects that are thought to be involved in innate immunity. In Drosophila, the Tep family is composed of 6 genes named Tep1-Tep6. In this study, we investigated the phylogeny, expression pattern and roles of these genes in the host defense of Drosophila. Protostomian Tep genes are clustered in 3 distinct branches, 1 of which is specific to mosquitoes. Most D. melanogaster Tep genes are expressed in hemocytes, can be induced in the fat body, and are expressed in specific regions of the hypodermis. This expression pattern is consistent with a role in innate immunity. However, we find that TEP1, TEP2, and TEP4 are not strictly required in the body cavity to fight several bacterial and fungal infections. One possibility is that Drosophila TEPs act redundantly or that their absence can be compensated by other components of the immune response. TEPs may thus provide a subtle selective advantage during evolution. Alternatively, they may be required in host defense against specific as yet unidentified natural pathogens of Drosophila. |
| 91. | Reichhart, Jean-Marc; Gubb, David; Leclerc, Vincent The Drosophila serpins: multiple functions in immunity and morphogenesis Journal Article Meth. Enzymol., 499 , pp. 205–225, 2011, ISSN: 1557-7988. @article{reichhart_drosophila_2011, title = {The Drosophila serpins: multiple functions in immunity and morphogenesis}, author = { Jean-Marc Reichhart and David Gubb and Vincent Leclerc}, doi = {10.1016/B978-0-12-386471-0.00011-0}, issn = {1557-7988}, year = {2011}, date = {2011-01-01}, journal = {Meth. Enzymol.}, volume = {499}, pages = {205--225}, abstract = {Members of the serpin superfamily of proteins have been found in all living organisms, although rarely in bacteria or fungi. They have been extensively studied in mammals, where many rapid physiological responses are regulated by inhibitory serpins. In addition to the inhibitory serpins, a large group of noninhibitory proteins with a conserved serpin fold have also been identified in mammals. These noninhibitory proteins have a wide range of functions, from storage proteins to molecular chaperones, hormone transporters, and tumor suppressors. In contrast, until recently, very little was known about insect serpins in general, or Drosophila serpins in particular. In the last decade, however, there has been an increasing interest in the serpin biology of insects. It is becoming clear that, like in mammals, a similar wide range of physiological responses are regulated in insects and that noninhibitory serpin-fold proteins also play key roles in insect biology. Drosophila is also an important model organism that can be used to study human pathologies (among which serpinopathies or other protein conformational diseases) and mechanisms of regulation of proteolytic cascades in health or to develop strategies for control of insect pests and disease vectors. As most of our knowledge on insect serpins comes from studies on the Drosophila immune response, we survey here the Drosophila serpin literature and describe the laboratory techniques that have been developed to study serpin-regulated responses in this model genetic organism.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Members of the serpin superfamily of proteins have been found in all living organisms, although rarely in bacteria or fungi. They have been extensively studied in mammals, where many rapid physiological responses are regulated by inhibitory serpins. In addition to the inhibitory serpins, a large group of noninhibitory proteins with a conserved serpin fold have also been identified in mammals. These noninhibitory proteins have a wide range of functions, from storage proteins to molecular chaperones, hormone transporters, and tumor suppressors. In contrast, until recently, very little was known about insect serpins in general, or Drosophila serpins in particular. In the last decade, however, there has been an increasing interest in the serpin biology of insects. It is becoming clear that, like in mammals, a similar wide range of physiological responses are regulated in insects and that noninhibitory serpin-fold proteins also play key roles in insect biology. Drosophila is also an important model organism that can be used to study human pathologies (among which serpinopathies or other protein conformational diseases) and mechanisms of regulation of proteolytic cascades in health or to develop strategies for control of insect pests and disease vectors. As most of our knowledge on insect serpins comes from studies on the Drosophila immune response, we survey here the Drosophila serpin literature and describe the laboratory techniques that have been developed to study serpin-regulated responses in this model genetic organism. |
2010 |
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Journal Articles |
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| 90. | Silverman, Gary A; Whisstock, James C; Bottomley, Stephen P; Huntington, James A; Kaiserman, Dion; Luke, Cliff J; Pak, Stephen C; Reichhart, Jean-Marc; Bird, Phillip I Serpins flex their muscle: I. Putting the clamps on proteolysis in diverse biological systems Journal Article J. Biol. Chem., 285 (32), pp. 24299–24305, 2010, ISSN: 1083-351X. @article{silverman_serpins_2010, title = {Serpins flex their muscle: I. Putting the clamps on proteolysis in diverse biological systems}, author = { Gary A. Silverman and James C. Whisstock and Stephen P. Bottomley and James A. Huntington and Dion Kaiserman and Cliff J. Luke and Stephen C. Pak and Jean-Marc Reichhart and Phillip I. Bird}, doi = {10.1074/jbc.R110.112771}, issn = {1083-351X}, year = {2010}, date = {2010-08-01}, journal = {J. Biol. Chem.}, volume = {285}, number = {32}, pages = {24299--24305}, abstract = {Serpins compose the largest superfamily of peptidase inhibitors and are well known as regulators of hemostasis and thrombolysis. Studies using model organisms, from plants to vertebrates, now show that serpins and their unique inhibitory mechanism and conformational flexibility are exploited to control proteolysis in molecular pathways associated with cell survival, development, and host defense. In addition, an increasing number of non-inhibitory serpins are emerging as important elements within a diversity of biological systems by serving as chaperones, hormone transporters, or anti-angiogenic factors.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Serpins compose the largest superfamily of peptidase inhibitors and are well known as regulators of hemostasis and thrombolysis. Studies using model organisms, from plants to vertebrates, now show that serpins and their unique inhibitory mechanism and conformational flexibility are exploited to control proteolysis in molecular pathways associated with cell survival, development, and host defense. In addition, an increasing number of non-inhibitory serpins are emerging as important elements within a diversity of biological systems by serving as chaperones, hormone transporters, or anti-angiogenic factors. |
| 89. | Whisstock, James C; Silverman, Gary A; Bird, Phillip I; Bottomley, Stephen P; Kaiserman, Dion; Luke, Cliff J; Pak, Stephen C; Reichhart, Jean-Marc; Huntington, James A Serpins flex their muscle: II. Structural insights into target peptidase recognition, polymerization, and transport functions Journal Article J. Biol. Chem., 285 (32), pp. 24307–24312, 2010, ISSN: 1083-351X. @article{whisstock_serpins_2010, title = {Serpins flex their muscle: II. Structural insights into target peptidase recognition, polymerization, and transport functions}, author = { James C. Whisstock and Gary A. Silverman and Phillip I. Bird and Stephen P. Bottomley and Dion Kaiserman and Cliff J. Luke and Stephen C. Pak and Jean-Marc Reichhart and James A. Huntington}, doi = {10.1074/jbc.R110.141408}, issn = {1083-351X}, year = {2010}, date = {2010-08-01}, journal = {J. Biol. Chem.}, volume = {285}, number = {32}, pages = {24307--24312}, abstract = {Inhibitory serpins are metastable proteins that undergo a substantial conformational rearrangement to covalently trap target peptidases. The serpin reactive center loop contributes a majority of the interactions that serpins make during the initial binding to target peptidases. However, structural studies on serpin-peptidase complexes reveal a broader set of contacts on the scaffold of inhibitory serpins that have substantial influence on guiding peptidase recognition. Structural and biophysical studies also reveal how aberrant serpin folding can lead to the formation of domain-swapped serpin multimers rather than the monomeric metastable state. Serpin domain swapping may therefore underlie the polymerization events characteristic of the serpinopathies. Finally, recent structural studies reveal how the serpin fold has been adapted for non-inhibitory functions such as hormone binding.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Inhibitory serpins are metastable proteins that undergo a substantial conformational rearrangement to covalently trap target peptidases. The serpin reactive center loop contributes a majority of the interactions that serpins make during the initial binding to target peptidases. However, structural studies on serpin-peptidase complexes reveal a broader set of contacts on the scaffold of inhibitory serpins that have substantial influence on guiding peptidase recognition. Structural and biophysical studies also reveal how aberrant serpin folding can lead to the formation of domain-swapped serpin multimers rather than the monomeric metastable state. Serpin domain swapping may therefore underlie the polymerization events characteristic of the serpinopathies. Finally, recent structural studies reveal how the serpin fold has been adapted for non-inhibitory functions such as hormone binding. |
| 88. | Garcia, Alvaro Baeza; Pierce, Raymond J; Gourbal, Benjamin; Werkmeister, Elisabeth; Colinet, Dominique; Reichhart, Jean-Marc; Dissous, Colette; Coustau, Christine Involvement of the cytokine MIF in the snail host immune response to the parasite Schistosoma mansoni Journal Article PLoS Pathog., 6 (9), pp. e1001115, 2010, ISSN: 1553-7374. @article{baeza_garcia_involvement_2010, title = {Involvement of the cytokine MIF in the snail host immune response to the parasite Schistosoma mansoni}, author = { Alvaro Baeza Garcia and Raymond J. Pierce and Benjamin Gourbal and Elisabeth Werkmeister and Dominique Colinet and Jean-Marc Reichhart and Colette Dissous and Christine Coustau}, doi = {10.1371/journal.ppat.1001115}, issn = {1553-7374}, year = {2010}, date = {2010-01-01}, journal = {PLoS Pathog.}, volume = {6}, number = {9}, pages = {e1001115}, abstract = {We have identified and characterized a Macrophage Migration Inhibitory Factor (MIF) family member in the Lophotrochozoan invertebrate, Biomphalaria glabrata, the snail intermediate host of the human blood fluke Schistosoma mansoni. In mammals, MIF is a widely expressed pleiotropic cytokine with potent pro-inflammatory properties that controls cell functions such as gene expression, proliferation or apoptosis. Here we show that the MIF protein from B. glabrata (BgMIF) is expressed in circulating immune defense cells (hemocytes) of the snail as well as in the B. glabrata embryonic (Bge) cell line that has hemocyte-like features. Recombinant BgMIF (rBgMIF) induced cell proliferation and inhibited NO-dependent p53-mediated apoptosis in Bge cells. Moreover, knock-down of BgMIF expression in Bge cells interfered with the in vitro encapsulation of S. mansoni sporocysts. Furthermore, the in vivo knock-down of BgMIF prevented the changes in circulating hemocyte populations that occur in response to an infection by S. mansoni miracidia and led to a significant increase in the parasite burden of the snails. These results provide the first functional evidence that a MIF ortholog is involved in an invertebrate immune response towards a parasitic infection and highlight the importance of cytokines in invertebrate-parasite interactions.}, keywords = {}, pubstate = {published}, tppubtype = {article} } We have identified and characterized a Macrophage Migration Inhibitory Factor (MIF) family member in the Lophotrochozoan invertebrate, Biomphalaria glabrata, the snail intermediate host of the human blood fluke Schistosoma mansoni. In mammals, MIF is a widely expressed pleiotropic cytokine with potent pro-inflammatory properties that controls cell functions such as gene expression, proliferation or apoptosis. Here we show that the MIF protein from B. glabrata (BgMIF) is expressed in circulating immune defense cells (hemocytes) of the snail as well as in the B. glabrata embryonic (Bge) cell line that has hemocyte-like features. Recombinant BgMIF (rBgMIF) induced cell proliferation and inhibited NO-dependent p53-mediated apoptosis in Bge cells. Moreover, knock-down of BgMIF expression in Bge cells interfered with the in vitro encapsulation of S. mansoni sporocysts. Furthermore, the in vivo knock-down of BgMIF prevented the changes in circulating hemocyte populations that occur in response to an infection by S. mansoni miracidia and led to a significant increase in the parasite burden of the snails. These results provide the first functional evidence that a MIF ortholog is involved in an invertebrate immune response towards a parasitic infection and highlight the importance of cytokines in invertebrate-parasite interactions. |
| 87. | Paquette, Nicholas; Broemer, Meike; Aggarwal, Kamna; Chen, Li; Husson, Marie; Ertürk-Hasdemir, Deniz; Reichhart, Jean-Marc; Meier, Pascal; Silverman, Neal Caspase-mediated cleavage, IAP binding, and ubiquitination: linking three mechanisms crucial for Drosophila NF-kappaB signaling Journal Article Mol. Cell, 37 (2), pp. 172–182, 2010, ISSN: 1097-4164. @article{paquette_caspase-mediated_2010, title = {Caspase-mediated cleavage, IAP binding, and ubiquitination: linking three mechanisms crucial for Drosophila NF-kappaB signaling}, author = { Nicholas Paquette and Meike Broemer and Kamna Aggarwal and Li Chen and Marie Husson and Deniz Ertürk-Hasdemir and Jean-Marc Reichhart and Pascal Meier and Neal Silverman}, doi = {10.1016/j.molcel.2009.12.036}, issn = {1097-4164}, year = {2010}, date = {2010-01-01}, journal = {Mol. Cell}, volume = {37}, number = {2}, pages = {172--182}, abstract = {Innate immune responses are critical for the immediate protection against microbial infection. In Drosophila, infection leads to the rapid and robust production of antimicrobial peptides through two NF-kappaB signaling pathways-IMD and Toll. The IMD pathway is triggered by DAP-type peptidoglycan, common to most Gram-negative bacteria. Signaling downstream from the peptidoglycan receptors is thought to involve K63 ubiquitination and caspase-mediated cleavage, but the molecular mechanisms remain obscure. We now show that PGN stimulation causes caspase-mediated cleavage of the imd protein, exposing a highly conserved IAP-binding motif (IBM) at its neo-N terminus. A functional IBM is required for the association of cleaved IMD with the ubiquitin E3-ligase DIAP2. Through its association with DIAP2, IMD is rapidly conjugated with K63-linked polyubiquitin chains. These results mechanistically connect caspase-mediated cleavage and K63 ubiquitination in immune-induced NF-kappaB signaling.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Innate immune responses are critical for the immediate protection against microbial infection. In Drosophila, infection leads to the rapid and robust production of antimicrobial peptides through two NF-kappaB signaling pathways-IMD and Toll. The IMD pathway is triggered by DAP-type peptidoglycan, common to most Gram-negative bacteria. Signaling downstream from the peptidoglycan receptors is thought to involve K63 ubiquitination and caspase-mediated cleavage, but the molecular mechanisms remain obscure. We now show that PGN stimulation causes caspase-mediated cleavage of the imd protein, exposing a highly conserved IAP-binding motif (IBM) at its neo-N terminus. A functional IBM is required for the association of cleaved IMD with the ubiquitin E3-ligase DIAP2. Through its association with DIAP2, IMD is rapidly conjugated with K63-linked polyubiquitin chains. These results mechanistically connect caspase-mediated cleavage and K63 ubiquitination in immune-induced NF-kappaB signaling. |
2009 |
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Journal Articles |
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| 86. | Shia, Alice K H; Glittenberg, Marcus; Thompson, Gavin; Weber, Alexander N R; Reichhart, Jean-Marc; Ligoxygakis, Petros Toll-dependent antimicrobial responses in Drosophila larval fat body require Spätzle secreted by haemocytes Journal Article J. Cell. Sci., 122 (Pt 24), pp. 4505–4515, 2009, ISSN: 1477-9137. @article{shia_toll-dependent_2009, title = {Toll-dependent antimicrobial responses in Drosophila larval fat body require Spätzle secreted by haemocytes}, author = {Alice K. H. Shia and Marcus Glittenberg and Gavin Thompson and Alexander N. R. Weber and Jean-Marc Reichhart and Petros Ligoxygakis}, doi = {10.1242/jcs.049155}, issn = {1477-9137}, year = {2009}, date = {2009-12-01}, journal = {J. Cell. Sci.}, volume = {122}, number = {Pt 24}, pages = {4505--4515}, abstract = {In Drosophila, the humoral response characterised by the synthesis of antimicrobial peptides (AMPs) in the fat body (the equivalent of the mammalian liver) and the cellular response mediated by haemocytes (blood cells) engaged in phagocytosis represent two major reactions that counter pathogens. Although considerable analysis has permitted the elucidation of mechanisms pertaining to the two responses individually, the mechanism of their coordination has been unclear. To characterise the signals with which infection might be communicated between blood cells and fat body, we ablated circulating haemocytes and defined the parameters of AMP gene activation in larvae. We found that targeted ablation of blood cells influenced the levels of AMP gene expression in the fat body following both septic injury and oral infection. Expression of the AMP gene drosomycin (a Toll target) was blocked when expression of the Toll ligand Spätzle was knocked down in haemocytes. These results show that in larvae, integration of the two responses in a systemic reaction depend on the production of a cytokine (spz), a process that strongly parallels the mammalian immune response.}, keywords = {}, pubstate = {published}, tppubtype = {article} } In Drosophila, the humoral response characterised by the synthesis of antimicrobial peptides (AMPs) in the fat body (the equivalent of the mammalian liver) and the cellular response mediated by haemocytes (blood cells) engaged in phagocytosis represent two major reactions that counter pathogens. Although considerable analysis has permitted the elucidation of mechanisms pertaining to the two responses individually, the mechanism of their coordination has been unclear. To characterise the signals with which infection might be communicated between blood cells and fat body, we ablated circulating haemocytes and defined the parameters of AMP gene activation in larvae. We found that targeted ablation of blood cells influenced the levels of AMP gene expression in the fat body following both septic injury and oral infection. Expression of the AMP gene drosomycin (a Toll target) was blocked when expression of the Toll ligand Spätzle was knocked down in haemocytes. These results show that in larvae, integration of the two responses in a systemic reaction depend on the production of a cytokine (spz), a process that strongly parallels the mammalian immune response. |
Incollections |
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| 85. | Leclerc, Vincent; Caldelari, Isabelle; Veresceaghina, N; Reichhart, Jean-Marc Phagocytosis in Drosophila melanogaster Immune Response. Incollection Phagocyte-pathogen Interactions, 33 , pp. 513–521, DG Russel and S. Gordon, Whasington, DC, 2009. @incollection{leclerc_phagocytosis_2009, title = {Phagocytosis in Drosophila melanogaster Immune Response.}, author = { Vincent Leclerc and Isabelle Caldelari and N. Veresceaghina and Jean-Marc Reichhart}, year = {2009}, date = {2009-01-01}, booktitle = {Phagocyte-pathogen Interactions}, volume = {33}, pages = {513--521}, publisher = {DG Russel and S. Gordon}, address = {Whasington, DC}, edition = {ASM Press}, keywords = {}, pubstate = {published}, tppubtype = {incollection} } |
2008 |
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| 84. | Deddouche, Safia; Matt, Nicolas ; Budd, Aidan ; Mueller, Stefanie ; Kemp, Cordula ; Galiana-Arnoux, Delphine ; Dostert, Catherine ; Antoniewski, Christophe ; Hoffmann, Jules A; Imler, Jean-Luc The DExD/Ħ-box helicase Dicer-2 mediates the induction of antiviral activity in drosophila Journal Article Nature Immunology, 9 (12), pp. 1425–1432, 2008, ISSN: 1529-2916. @article{deddouche_dexd/h-box_2008, title = {The DExD/Ħ-box helicase Dicer-2 mediates the induction of antiviral activity in drosophila}, author = { Safia Deddouche and Nicolas Matt and Aidan Budd and Stefanie Mueller and Cordula Kemp and Delphine Galiana-Arnoux and Catherine Dostert and Christophe Antoniewski and Jules A. Hoffmann and Jean-Luc Imler}, doi = {10.1038/ni.1664}, issn = {1529-2916}, year = {2008}, date = {2008-12-01}, journal = {Nature Immunology}, volume = {9}, number = {12}, pages = {1425--1432}, abstract = {Drosophila, like other invertebrates and plants, relies mainly on RNA interference for its defense against viruses. In flies, viral infection also triggers the expression of many genes. One of the genes induced, Vago, encodes a 18-kilodalton cysteine-rich polypeptide. Here we provide genetic evidence that the Vago gene product controlled viral load in the fat body after infection with drosophila C virus. Induction of Vago was dependent on the helicase Dicer-2. Dicer-2 belongs to the same DExD/H-box helicase family as do the RIG-I-like receptors, which sense viral infection and mediate interferon induction in mammals. We propose that this family represents an evolutionary conserved set of sensors that detect viral nucleic acids and direct antiviral responses.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Drosophila, like other invertebrates and plants, relies mainly on RNA interference for its defense against viruses. In flies, viral infection also triggers the expression of many genes. One of the genes induced, Vago, encodes a 18-kilodalton cysteine-rich polypeptide. Here we provide genetic evidence that the Vago gene product controlled viral load in the fat body after infection with drosophila C virus. Induction of Vago was dependent on the helicase Dicer-2. Dicer-2 belongs to the same DExD/H-box helicase family as do the RIG-I-like receptors, which sense viral infection and mediate interferon induction in mammals. We propose that this family represents an evolutionary conserved set of sensors that detect viral nucleic acids and direct antiviral responses. |
| 83. | Chamy, Laure El; Leclerc, Vincent; Caldelari, Isabelle; Reichhart, Jean-Marc Sensing of 'danger signals' and pathogen-associated molecular patterns defines binary signaling pathways 'upstream' of Toll Journal Article Nat. Immunol., 9 (10), pp. 1165–1170, 2008, ISSN: 1529-2916. @article{el_chamy_sensing_2008, title = {Sensing of 'danger signals' and pathogen-associated molecular patterns defines binary signaling pathways 'upstream' of Toll}, author = { Laure El Chamy and Vincent Leclerc and Isabelle Caldelari and Jean-Marc Reichhart}, doi = {10.1038/ni.1643}, issn = {1529-2916}, year = {2008}, date = {2008-10-01}, journal = {Nat. Immunol.}, volume = {9}, number = {10}, pages = {1165--1170}, abstract = {In drosophila, molecular determinants from fungi and Gram-positive bacteria are detected by circulating pattern-recognition receptors. Published findings suggest that such pattern-recognition receptors activate as-yet-unidentified serine-protease cascades that culminate in the cleavage of Spätzle, the endogenous Toll receptor ligand, and trigger the immune response. We demonstrate here that the protease Grass defines a common activation cascade for the detection of fungi and Gram-positive bacteria mediated by pattern-recognition receptors. The serine protease Persephone, shown before to be specific for fungal detection in a cascade activated by secreted fungal proteases, was also required for the sensing of proteases elicited by bacteria in the hemolymph. Hence, Persephone defines a parallel proteolytic cascade activated by 'danger signals' such as abnormal proteolytic activities.}, keywords = {}, pubstate = {published}, tppubtype = {article} } In drosophila, molecular determinants from fungi and Gram-positive bacteria are detected by circulating pattern-recognition receptors. Published findings suggest that such pattern-recognition receptors activate as-yet-unidentified serine-protease cascades that culminate in the cleavage of Spätzle, the endogenous Toll receptor ligand, and trigger the immune response. We demonstrate here that the protease Grass defines a common activation cascade for the detection of fungi and Gram-positive bacteria mediated by pattern-recognition receptors. The serine protease Persephone, shown before to be specific for fungal detection in a cascade activated by secreted fungal proteases, was also required for the sensing of proteases elicited by bacteria in the hemolymph. Hence, Persephone defines a parallel proteolytic cascade activated by 'danger signals' such as abnormal proteolytic activities. |
| 82. | Goto, Akira; Matsushita, Kazufumi ; Gesellchen, Viola ; Chamy, Laure El ; Kuttenkeuler, David ; Takeuchi, Osamu ; Hoffmann, Jules A; Akira, Shizuo ; Boutros, Michael ; Reichhart, Jean-Marc Akirins are highly conserved nuclear proteins required for NF-kappaB-dependent gene expression in drosophila and mice Journal Article Nat. Immunol., 9 (1), pp. 97–104, 2008, ISSN: 1529-2916. @article{goto_akirins_2008, title = {Akirins are highly conserved nuclear proteins required for NF-kappaB-dependent gene expression in drosophila and mice}, author = { Akira Goto and Kazufumi Matsushita and Viola Gesellchen and Laure El Chamy and David Kuttenkeuler and Osamu Takeuchi and Jules A. Hoffmann and Shizuo Akira and Michael Boutros and Jean-Marc Reichhart}, doi = {10.1038/ni1543}, issn = {1529-2916}, year = {2008}, date = {2008-01-01}, journal = {Nat. Immunol.}, volume = {9}, number = {1}, pages = {97--104}, abstract = {During a genome-wide screen with RNA-mediated interference, we isolated CG8580 as a gene involved in the innate immune response of Drosophila melanogaster. CG8580, which we called Akirin, encoded a protein that acted in parallel with the NF-kappaB transcription factor downstream of the Imd pathway and was required for defense against Gram-negative bacteria. Akirin is highly conserved, and the human genome contains two homologs, one of which was able to rescue the loss-of-function phenotype in drosophila cells. Akirins were strictly localized to the nucleus. Knockout of both Akirin homologs in mice showed that one had an essential function downstream of the Toll-like receptor, tumor necrosis factor and interleukin (IL)-1beta signaling pathways leading to the production of IL-6. Thus, Akirin is a conserved nuclear factor required for innate immune responses.}, keywords = {}, pubstate = {published}, tppubtype = {article} } During a genome-wide screen with RNA-mediated interference, we isolated CG8580 as a gene involved in the innate immune response of Drosophila melanogaster. CG8580, which we called Akirin, encoded a protein that acted in parallel with the NF-kappaB transcription factor downstream of the Imd pathway and was required for defense against Gram-negative bacteria. Akirin is highly conserved, and the human genome contains two homologs, one of which was able to rescue the loss-of-function phenotype in drosophila cells. Akirins were strictly localized to the nucleus. Knockout of both Akirin homologs in mice showed that one had an essential function downstream of the Toll-like receptor, tumor necrosis factor and interleukin (IL)-1beta signaling pathways leading to the production of IL-6. Thus, Akirin is a conserved nuclear factor required for innate immune responses. |
2007 |
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Incollections |
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| 81. | Gubb, David; Robertson, Andrew S; Troxler, Laurent; Reichhart, Jean-Marc Drosophila Serpins: Regulatory Cascades in Innate Immunity and Morphogenesis Incollection Molecular and Cellular Aspects of the Serpinopathies and Disorders in Serpin Activity, pp. 207–227, Silverman GA and Lomas DA, London UK, 2007. @incollection{gubb_drosophila_2007, title = {Drosophila Serpins: Regulatory Cascades in Innate Immunity and Morphogenesis}, author = { David Gubb and Andrew S. Robertson and Laurent Troxler and Jean-Marc Reichhart}, year = {2007}, date = {2007-01-01}, booktitle = {Molecular and Cellular Aspects of the Serpinopathies and Disorders in Serpin Activity}, pages = {207--227}, publisher = {Silverman GA and Lomas DA}, address = {London UK}, edition = {World Scientific Pub.}, keywords = {}, pubstate = {published}, tppubtype = {incollection} } |
2006 |
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| 80. | Gottar, Marie; Gobert, Vanessa ; Matskevich, Alexey A; Reichhart, Jean-Marc ; Wang, Chengshu ; Butt, Tariq M; Belvin, Marcia ; Hoffmann, Jules A; Ferrandon, Dominique Dual detection of fungal infections in Drosophila via recognition of glucans and sensing of virulence factors Journal Article Cell, 127 (7), pp. 1425–1437, 2006, ISSN: 0092-8674. @article{gottar_dual_2006, title = {Dual detection of fungal infections in Drosophila via recognition of glucans and sensing of virulence factors}, author = { Marie Gottar and Vanessa Gobert and Alexey A. Matskevich and Jean-Marc Reichhart and Chengshu Wang and Tariq M. Butt and Marcia Belvin and Jules A. Hoffmann and Dominique Ferrandon}, doi = {10.1016/j.cell.2006.10.046}, issn = {0092-8674}, year = {2006}, date = {2006-12-01}, journal = {Cell}, volume = {127}, number = {7}, pages = {1425--1437}, abstract = {The Drosophila immune system discriminates between various types of infections and activates appropriate signal transduction pathways to combat the invading microorganisms. The Toll pathway is required for the host response against fungal and most Gram-positive bacterial infections. The sensing of Gram-positive bacteria is mediated by the pattern recognition receptors PGRP-SA and GNBP1 that cooperate to detect the presence of infections in the host. Here, we report that GNBP3 is a pattern recognition receptor that is required for the detection of fungal cell wall components. Strikingly, we find that there is a second, parallel pathway acting jointly with GNBP3. The Drosophila Persephone protease activates the Toll pathway when proteolytically matured by the secreted fungal virulence factor PR1. Thus, the detection of fungal infections in Drosophila relies both on the recognition of invariant microbial patterns and on monitoring the effects of virulence factors on the host.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The Drosophila immune system discriminates between various types of infections and activates appropriate signal transduction pathways to combat the invading microorganisms. The Toll pathway is required for the host response against fungal and most Gram-positive bacterial infections. The sensing of Gram-positive bacteria is mediated by the pattern recognition receptors PGRP-SA and GNBP1 that cooperate to detect the presence of infections in the host. Here, we report that GNBP3 is a pattern recognition receptor that is required for the detection of fungal cell wall components. Strikingly, we find that there is a second, parallel pathway acting jointly with GNBP3. The Drosophila Persephone protease activates the Toll pathway when proteolytically matured by the secreted fungal virulence factor PR1. Thus, the detection of fungal infections in Drosophila relies both on the recognition of invariant microbial patterns and on monitoring the effects of virulence factors on the host. |
| 79. | Leclerc, Vincent; Pelte, Nadège ; Chamy, Laure El ; Martinelli, Cosimo ; Ligoxygakis, Petros ; Hoffmann, Jules A; Reichhart, Jean-Marc Prophenoloxidase activation is not required for survival to microbial infections in Drosophila Journal Article EMBO Rep., 7 (2), pp. 231–235, 2006, ISSN: 1469-221X. @article{leclerc_prophenoloxidase_2006, title = {Prophenoloxidase activation is not required for survival to microbial infections in Drosophila}, author = { Vincent Leclerc and Nadège Pelte and Laure El Chamy and Cosimo Martinelli and Petros Ligoxygakis and Jules A. Hoffmann and Jean-Marc Reichhart}, doi = {10.1038/sj.embor.7400592}, issn = {1469-221X}, year = {2006}, date = {2006-02-01}, journal = {EMBO Rep.}, volume = {7}, number = {2}, pages = {231--235}, abstract = {The antimicrobial defence of Drosophila relies on cellular and humoral processes, of which the inducible synthesis of antimicrobial peptides has attracted interest in recent years. Another potential line of defence is the activation, by a proteolytic cascade, of phenoloxidase, which leads to the production of quinones and melanin. However, in spite of several publications on this subject, the contribution of phenoloxidase activation to resistance to infections has not been established under appropriate in vivo conditions. Here, we have isolated the first Drosophila mutant for a prophenoloxidase-activating enzyme (PAE1). In contrast to wild-type flies, PAE1 mutants fail to activate phenoloxidase in the haemolymph following microbial challenge. Surprisingly, we find that these mutants are as resistant to infections as wild-type flies, in the total absence of circulating phenoloxidase activity. This raises the question with regard to the precise function of phenoloxidase activation in defence, if any.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The antimicrobial defence of Drosophila relies on cellular and humoral processes, of which the inducible synthesis of antimicrobial peptides has attracted interest in recent years. Another potential line of defence is the activation, by a proteolytic cascade, of phenoloxidase, which leads to the production of quinones and melanin. However, in spite of several publications on this subject, the contribution of phenoloxidase activation to resistance to infections has not been established under appropriate in vivo conditions. Here, we have isolated the first Drosophila mutant for a prophenoloxidase-activating enzyme (PAE1). In contrast to wild-type flies, PAE1 mutants fail to activate phenoloxidase in the haemolymph following microbial challenge. Surprisingly, we find that these mutants are as resistant to infections as wild-type flies, in the total absence of circulating phenoloxidase activity. This raises the question with regard to the precise function of phenoloxidase activation in defence, if any. |
| 78. | Pelte, Nadège; Robertson, Andrew S; Zou, Zhen; Belorgey, Didier; Dafforn, Timothy R; Jiang, Haobo; Lomas, David; Reichhart, Jean-Marc; Gubb, David Immune challenge induces N-terminal cleavage of the Drosophila serpin Necrotic Journal Article Insect Biochem. Mol. Biol., 36 (1), pp. 37–46, 2006, ISSN: 0965-1748. @article{pelte_immune_2006, title = {Immune challenge induces N-terminal cleavage of the Drosophila serpin Necrotic}, author = { Nadège Pelte and Andrew S. Robertson and Zhen Zou and Didier Belorgey and Timothy R. Dafforn and Haobo Jiang and David Lomas and Jean-Marc Reichhart and David Gubb}, doi = {10.1016/j.ibmb.2005.10.004}, issn = {0965-1748}, year = {2006}, date = {2006-01-01}, journal = {Insect Biochem. Mol. Biol.}, volume = {36}, number = {1}, pages = {37--46}, abstract = {The Drosophila Necrotic protein is a serine proteinase inhibitor, which regulates the Toll-mediated innate immune response. Necrotic specifically inhibits an extracellular serine proteinase cascade leading to activation of the Toll ligand, Spätzle. Necrotic carries a polyglutamine extension amino-terminal to the core serpin structure. We show here that cleavage of this N-terminal extension occurs following immune challenge. This modification is blocked in PGRP-SA(semmelweiss) mutants after Gram-positive bacterial challenge and in persephone mutants after fungal or Gram-positive bacterial challenge, indicating that activation of either of the Toll pathway upstream branches induces N-terminal cleavage of the serpin. The absolute requirement of persephone gene product for this cleavage indicates that Gram-positive bacteria activate a redundant set of proteinases upstream of Toll. Both full-length Necrotic and the core serpin are active inhibitors of a range of serine proteinases: the highest affinity being for cathepsin G and elastases. We found a 13-fold increase in the specificity of the core serpin over that of full-length Necrotic for one of the tested proteinases (porcine pancreatic elastase). This finding indicates that cleavage of the Necrotic amino-terminal extension might modulate Toll activation following the initial immune response.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The Drosophila Necrotic protein is a serine proteinase inhibitor, which regulates the Toll-mediated innate immune response. Necrotic specifically inhibits an extracellular serine proteinase cascade leading to activation of the Toll ligand, Spätzle. Necrotic carries a polyglutamine extension amino-terminal to the core serpin structure. We show here that cleavage of this N-terminal extension occurs following immune challenge. This modification is blocked in PGRP-SA(semmelweiss) mutants after Gram-positive bacterial challenge and in persephone mutants after fungal or Gram-positive bacterial challenge, indicating that activation of either of the Toll pathway upstream branches induces N-terminal cleavage of the serpin. The absolute requirement of persephone gene product for this cleavage indicates that Gram-positive bacteria activate a redundant set of proteinases upstream of Toll. Both full-length Necrotic and the core serpin are active inhibitors of a range of serine proteinases: the highest affinity being for cathepsin G and elastases. We found a 13-fold increase in the specificity of the core serpin over that of full-length Necrotic for one of the tested proteinases (porcine pancreatic elastase). This finding indicates that cleavage of the Necrotic amino-terminal extension might modulate Toll activation following the initial immune response. |
2005 |
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| 77. | Reichhart, Jean-Marc Tip of another iceberg: Drosophila serpins Journal Article Trends Cell Biol., 15 (12), pp. 659–665, 2005, ISSN: 0962-8924. @article{reichhart_tip_2005, title = {Tip of another iceberg: Drosophila serpins}, author = { Jean-Marc Reichhart}, doi = {10.1016/j.tcb.2005.10.001}, issn = {0962-8924}, year = {2005}, date = {2005-12-01}, journal = {Trends Cell Biol.}, volume = {15}, number = {12}, pages = {659--665}, abstract = {Serpins are serine protease inhibitors with a conserved structure that have been identified in nearly all species and act as suicide substrates by binding covalently to their target proteases. Serpins regulate various physiological processes and defence mechanisms. In humans, several serpin mutations are linked to diseases. The genome of Drosophila melanogaster encodes 29 serpins and even more serine proteases. To date, three serpins have been investigated in detail. Spn27A controls the Toll pathway during early development and is involved in defence reactions in adult flies. SPN42DaA is an inhibitor of furin, a subtilisin-like convertase that is required for pro-protein maturation. Spn43Ac controls the Toll pathway during the immune response. In each case, Drosophila genetics has shed new light on the function of these serine protease inhibitors.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Serpins are serine protease inhibitors with a conserved structure that have been identified in nearly all species and act as suicide substrates by binding covalently to their target proteases. Serpins regulate various physiological processes and defence mechanisms. In humans, several serpin mutations are linked to diseases. The genome of Drosophila melanogaster encodes 29 serpins and even more serine proteases. To date, three serpins have been investigated in detail. Spn27A controls the Toll pathway during early development and is involved in defence reactions in adult flies. SPN42DaA is an inhibitor of furin, a subtilisin-like convertase that is required for pro-protein maturation. Spn43Ac controls the Toll pathway during the immune response. In each case, Drosophila genetics has shed new light on the function of these serine protease inhibitors. |
| 76. | Kocks, Christine; Cho, Ju Hyun ; Nehme, Nadine ; Ulvila, Johanna ; Pearson, Alan M; Meister, Marie ; Strom, Charles ; Conto, Stephanie L; Hetru, Charles ; Stuart, Lynda M; Stehle, Thilo ; Hoffmann, Jules A; Reichhart, Jean-Marc ; Ferrandon, Dominique ; Rämet, Mika ; Ezekowitz, Alan R B Eater, a transmembrane protein mediating phagocytosis of bacterial pathogens in Drosophila Journal Article Cell, 123 (2), pp. 335–346, 2005, ISSN: 0092-8674. @article{kocks_eater_2005, title = {Eater, a transmembrane protein mediating phagocytosis of bacterial pathogens in Drosophila}, author = { Christine Kocks and Ju Hyun Cho and Nadine Nehme and Johanna Ulvila and Alan M. Pearson and Marie Meister and Charles Strom and Stephanie L. Conto and Charles Hetru and Lynda M. Stuart and Thilo Stehle and Jules A. Hoffmann and Jean-Marc Reichhart and Dominique Ferrandon and Mika Rämet and R. Alan B. Ezekowitz}, doi = {10.1016/j.cell.2005.08.034}, issn = {0092-8674}, year = {2005}, date = {2005-10-01}, journal = {Cell}, volume = {123}, number = {2}, pages = {335--346}, abstract = {Phagocytosis is a complex, evolutionarily conserved process that plays a central role in host defense against infection. We have identified a predicted transmembrane protein, Eater, which is involved in phagocytosis in Drosophila. Transcriptional silencing of the eater gene in a macrophage cell line led to a significant reduction in the binding and internalization of bacteria. Moreover, the N terminus of the Eater protein mediated direct microbial binding which could be inhibited with scavenger receptor ligands, acetylated, and oxidized low-density lipoprotein. In vivo, eater expression was restricted to blood cells. Flies lacking the eater gene displayed normal responses in NF-kappaB-like Toll and IMD signaling pathways but showed impaired phagocytosis and decreased survival after bacterial infection. Our results suggest that Eater is a major phagocytic receptor for a broad range of bacterial pathogens in Drosophila and provide a powerful model to address the role of phagocytosis in vivo.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Phagocytosis is a complex, evolutionarily conserved process that plays a central role in host defense against infection. We have identified a predicted transmembrane protein, Eater, which is involved in phagocytosis in Drosophila. Transcriptional silencing of the eater gene in a macrophage cell line led to a significant reduction in the binding and internalization of bacteria. Moreover, the N terminus of the Eater protein mediated direct microbial binding which could be inhibited with scavenger receptor ligands, acetylated, and oxidized low-density lipoprotein. In vivo, eater expression was restricted to blood cells. Flies lacking the eater gene displayed normal responses in NF-kappaB-like Toll and IMD signaling pathways but showed impaired phagocytosis and decreased survival after bacterial infection. Our results suggest that Eater is a major phagocytic receptor for a broad range of bacterial pathogens in Drosophila and provide a powerful model to address the role of phagocytosis in vivo. |
| 75. | Royet, Julien; Reichhart, Jean-Marc ; Hoffmann, Jules A Sensing and signaling during infection in Drosophila Journal Article Curr. Opin. Immunol., 17 (1), pp. 11–17, 2005, ISSN: 0952-7915. @article{royet_sensing_2005, title = {Sensing and signaling during infection in Drosophila}, author = { Julien Royet and Jean-Marc Reichhart and Jules A. Hoffmann}, doi = {10.1016/j.coi.2004.12.002}, issn = {0952-7915}, year = {2005}, date = {2005-02-01}, journal = {Curr. Opin. Immunol.}, volume = {17}, number = {1}, pages = {11--17}, abstract = {Most of the progress in dissecting the Drosophila antimicrobial response over the past decade has centered around intracellular signaling pathways in immune response tissues and expression of genes encoding antimicrobial peptide genes. The past few years, however, have witnessed significant advances in our understanding of the recognition of microbial invaders and subsequent activation of signaling cascades. In particular, the roles of peptidoglycan recognition proteins, which have known homologues in mammals, have been recognized and examined at the structural and functional levels.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Most of the progress in dissecting the Drosophila antimicrobial response over the past decade has centered around intracellular signaling pathways in immune response tissues and expression of genes encoding antimicrobial peptide genes. The past few years, however, have witnessed significant advances in our understanding of the recognition of microbial invaders and subsequent activation of signaling cascades. In particular, the roles of peptidoglycan recognition proteins, which have known homologues in mammals, have been recognized and examined at the structural and functional levels. |
| 74. | Martinelli, Cosimo; Reichhart, Jean-Marc Evolution and integration of innate immune systems from fruit flies to man: lessons and questions Journal Article J. Endotoxin Res., 11 (4), pp. 243–248, 2005, ISSN: 0968-0519. @article{martinelli_evolution_2005, title = {Evolution and integration of innate immune systems from fruit flies to man: lessons and questions}, author = { Cosimo Martinelli and Jean-Marc Reichhart}, doi = {10.1179/096805105X37411}, issn = {0968-0519}, year = {2005}, date = {2005-01-01}, journal = {J. Endotoxin Res.}, volume = {11}, number = {4}, pages = {243--248}, abstract = {Despite broad differences in morphology, ecology and behavior, the fruit fly Drosophila melanogaster and humans show a remarkably high degree of conservation for many molecular, cellular, and developmental aspects of their biology. During the last decade, similarities have also been discovered in some of the mechanisms regulating their innate immune system. These parallels regard mainly the Toll-like receptor family and the intracellular signaling pathways involved in the control of the immune response. However, if the overall similarities are important, the detailed pathogen recognition mechanisms differ significantly between fly and humans, highlighting a complicated evolutionary history of the metazoan innate defenses. In this review, we will discuss the main similarities and differences between the two types of organisms. We hope that this current knowledge will be used as a starting point for a more comprehensive view of innate immunity within the broad variety of metazoan phyla.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Despite broad differences in morphology, ecology and behavior, the fruit fly Drosophila melanogaster and humans show a remarkably high degree of conservation for many molecular, cellular, and developmental aspects of their biology. During the last decade, similarities have also been discovered in some of the mechanisms regulating their innate immune system. These parallels regard mainly the Toll-like receptor family and the intracellular signaling pathways involved in the control of the immune response. However, if the overall similarities are important, the detailed pathogen recognition mechanisms differ significantly between fly and humans, highlighting a complicated evolutionary history of the metazoan innate defenses. In this review, we will discuss the main similarities and differences between the two types of organisms. We hope that this current knowledge will be used as a starting point for a more comprehensive view of innate immunity within the broad variety of metazoan phyla. |
2004 |
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| 73. | Leclerc, Vincent; Reichhart, Jean-Marc The immune response of Drosophila melanogaster Journal Article Immunol. Rev., 198 , pp. 59–71, 2004, ISSN: 0105-2896. @article{leclerc_immune_2004, title = {The immune response of Drosophila melanogaster}, author = { Vincent Leclerc and Jean-Marc Reichhart}, issn = {0105-2896}, year = {2004}, date = {2004-04-01}, journal = {Immunol. Rev.}, volume = {198}, pages = {59--71}, abstract = {The response of the fruit fly Drosophila melanogaster to various microorganism infections relies on a multilayered defense. The epithelia constitute a first and efficient barrier. Innate immunity is activated when microorganisms succeed in entering the body cavity of the fly. Invading microorganisms are killed by the combined action of cellular and humoral processes. They are phagocytosed by specialized blood cells, surrounded by toxic melanin, or lysed by antibacterial peptides secreted into the hemolymph by fat body cells. During the last few years, research has focused on the mechanisms of microbial recognition by various pattern recognition receptors and of the subsequent induction of antimicrobial peptide expression. The cellular arm of the Drosophila innate immune system, which was somehow neglected, now constitutes the new frontier.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The response of the fruit fly Drosophila melanogaster to various microorganism infections relies on a multilayered defense. The epithelia constitute a first and efficient barrier. Innate immunity is activated when microorganisms succeed in entering the body cavity of the fly. Invading microorganisms are killed by the combined action of cellular and humoral processes. They are phagocytosed by specialized blood cells, surrounded by toxic melanin, or lysed by antibacterial peptides secreted into the hemolymph by fat body cells. During the last few years, research has focused on the mechanisms of microbial recognition by various pattern recognition receptors and of the subsequent induction of antimicrobial peptide expression. The cellular arm of the Drosophila innate immune system, which was somehow neglected, now constitutes the new frontier. |
| 72. | Montagnani, C; Kappler, Christine; Reichhart, Jean-Marc; Escoubas, J M Cg-Rel, the first Rel/NF-kappaB homolog characterized in a mollusk, the Pacific oyster Crassostrea gigas. Journal Article FEBS Lett., 561 , pp. 75–82, 2004. @article{montagnani_cg-rel_2004, title = {Cg-Rel, the first Rel/NF-kappaB homolog characterized in a mollusk, the Pacific oyster Crassostrea gigas.}, author = { C. Montagnani and Christine Kappler and Jean-Marc Reichhart and J. M. Escoubas}, year = {2004}, date = {2004-01-01}, journal = {FEBS Lett.}, volume = {561}, pages = {75--82}, abstract = {We report here the identification and functional characterization of Cg-Rel, a gene encoding the Crassostrea gigas homolog of Rel/NF-kappaB transcription factors found in insects and mammals. Sequence and phylogenetic analysis showed that Cg-Rel shares the structural organization of Rel/NF-kappaB transcription factors of class II. It includes a Rel homology domain as well as a C-terminal transactivation domain (TD). Overexpression of Cg-Rel in the Drosophila S2 cell line activated the expression of a NF-kappaB-dependent reporter gene, whereas transfection with a Cg-Rel construct containing a C-terminal deletion of the TD or using a reporter gene with mutated kappaB binding sites failed to activate expression. These results suggest that Cg-Rel is a functional member of the Rel family of transcription factors, making this the sixth structurally homologous component of the Rel/NF-kappaB pathway characterized in C. gigas. Based on homology to other invertebrates' Rel/NF-kappaB cascade, the function of the oyster pathway may serve to regulate genes involved in innate defense and/or development. These findings serve to highlight a potentially important regulatory pathway to the study of oyster immunology, hence allowing comparison of the immune system in vertebrates and invertebrates, an important key issue to understand its evolution.}, keywords = {}, pubstate = {published}, tppubtype = {article} } We report here the identification and functional characterization of Cg-Rel, a gene encoding the Crassostrea gigas homolog of Rel/NF-kappaB transcription factors found in insects and mammals. Sequence and phylogenetic analysis showed that Cg-Rel shares the structural organization of Rel/NF-kappaB transcription factors of class II. It includes a Rel homology domain as well as a C-terminal transactivation domain (TD). Overexpression of Cg-Rel in the Drosophila S2 cell line activated the expression of a NF-kappaB-dependent reporter gene, whereas transfection with a Cg-Rel construct containing a C-terminal deletion of the TD or using a reporter gene with mutated kappaB binding sites failed to activate expression. These results suggest that Cg-Rel is a functional member of the Rel family of transcription factors, making this the sixth structurally homologous component of the Rel/NF-kappaB pathway characterized in C. gigas. Based on homology to other invertebrates' Rel/NF-kappaB cascade, the function of the oyster pathway may serve to regulate genes involved in innate defense and/or development. These findings serve to highlight a potentially important regulatory pathway to the study of oyster immunology, hence allowing comparison of the immune system in vertebrates and invertebrates, an important key issue to understand its evolution. |
| 71. | Reichhart, Jean-Marc Guest Editor of the Special Issue on Innate Immunity. Journal Article Mol. Immunol., 40 , pp. 843, 2004. @article{reichhart_guest_2004, title = {Guest Editor of the Special Issue on Innate Immunity.}, author = { Jean-Marc Reichhart}, year = {2004}, date = {2004-01-01}, journal = {Mol. Immunol.}, volume = {40}, pages = {843}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
| 70. | Imler, Jean-Luc; Ferrandon, Dominique ; Royet, Julien ; Reichhart, Jean-Marc ; Hetru, Charles ; Hoffmann, Jules A Toll-dependent and Toll-independent immune responses in Drosophila Journal Article Journal of Endotoxin Research, 10 (4), pp. 241–246, 2004, ISSN: 0968-0519. @article{imler_toll-dependent_2004, title = {Toll-dependent and Toll-independent immune responses in Drosophila}, author = { Jean-Luc Imler and Dominique Ferrandon and Julien Royet and Jean-Marc Reichhart and Charles Hetru and Jules A. Hoffmann}, doi = {10.1179/096805104225005887}, issn = {0968-0519}, year = {2004}, date = {2004-01-01}, journal = {Journal of Endotoxin Research}, volume = {10}, number = {4}, pages = {241--246}, abstract = {The multifaceted response of the fruitfly Drosophila melanogaster to infection by a wide range of microbes is complex and remarkably efficient. Its most prominent aspect is the immune-inducible expression of a set of potent antimicrobial peptides. Genetic analysis of the regulation of the genes encoding these peptides has led to the identification of the receptor Toll as an essential component of the fly's host defense system. In addition, these studies have revealed that the response to Gram-negative bacterial infections involves Toll-independent mechanisms, and that the sensing of infection involves two structurally distinct sets of molecules--the PGRPs and the GNBPs/betaGRPs.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The multifaceted response of the fruitfly Drosophila melanogaster to infection by a wide range of microbes is complex and remarkably efficient. Its most prominent aspect is the immune-inducible expression of a set of potent antimicrobial peptides. Genetic analysis of the regulation of the genes encoding these peptides has led to the identification of the receptor Toll as an essential component of the fly's host defense system. In addition, these studies have revealed that the response to Gram-negative bacterial infections involves Toll-independent mechanisms, and that the sensing of infection involves two structurally distinct sets of molecules--the PGRPs and the GNBPs/betaGRPs. |
2003 |
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| 69. | Ligoxygakis, Petros; Roth, Siegfried; Reichhart, Jean-Marc A serpin regulates dorsal-ventral axis formation in the Drosophila embryo Journal Article Curr. Biol., 13 (23), pp. 2097–2102, 2003, ISSN: 0960-9822. @article{ligoxygakis_serpin_2003, title = {A serpin regulates dorsal-ventral axis formation in the Drosophila embryo}, author = { Petros Ligoxygakis and Siegfried Roth and Jean-Marc Reichhart}, issn = {0960-9822}, year = {2003}, date = {2003-12-01}, journal = {Curr. Biol.}, volume = {13}, number = {23}, pages = {2097--2102}, abstract = {Extracellular serine protease cascades have evolved in vertebrates and invertebrates to mediate rapid, local reactions to physiological or pathological cues. The serine protease cascade that triggers the Toll signaling pathway in Drosophila embryogenesis shares several organizational characteristics with those involved in mammalian complement and blood clotting. One of the hallmarks of such cascades is their regulation by serine protease inhibitors (serpins). Serpins act as suicide substrates and are cleaved by their target protease, forming an essentially irreversible 1:1 complex. The biological importance of serpins is highlighted by serpin dysfunction diseases, such as thrombosis caused by a deficiency in antithrombin. Here, we describe how a serpin controls the serine protease cascade, leading to Toll pathway activation. Female flies deficient in Serpin-27A produce embryos that lack dorsal-ventral polarity and show uniform high levels of Toll signaling. Since this serpin has been recently shown to restrain an immune reaction in the blood of Drosophila, it demonstrates that proteolysis can be regulated by the same serpin in different biological contexts.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Extracellular serine protease cascades have evolved in vertebrates and invertebrates to mediate rapid, local reactions to physiological or pathological cues. The serine protease cascade that triggers the Toll signaling pathway in Drosophila embryogenesis shares several organizational characteristics with those involved in mammalian complement and blood clotting. One of the hallmarks of such cascades is their regulation by serine protease inhibitors (serpins). Serpins act as suicide substrates and are cleaved by their target protease, forming an essentially irreversible 1:1 complex. The biological importance of serpins is highlighted by serpin dysfunction diseases, such as thrombosis caused by a deficiency in antithrombin. Here, we describe how a serpin controls the serine protease cascade, leading to Toll pathway activation. Female flies deficient in Serpin-27A produce embryos that lack dorsal-ventral polarity and show uniform high levels of Toll signaling. Since this serpin has been recently shown to restrain an immune reaction in the blood of Drosophila, it demonstrates that proteolysis can be regulated by the same serpin in different biological contexts. |
| 68. | Reichhart, Jean-Marc TLR5 takes aim at bacterial propeller Journal Article Nat. Immunol., 4 (12), pp. 1159–1160, 2003, ISSN: 1529-2908. @article{reichhart_tlr5_2003, title = {TLR5 takes aim at bacterial propeller}, author = { Jean-Marc Reichhart}, doi = {10.1038/ni1203-1159}, issn = {1529-2908}, year = {2003}, date = {2003-12-01}, journal = {Nat. Immunol.}, volume = {4}, number = {12}, pages = {1159--1160}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
| 67. | Royet, Julien; Reichhart, Jean-Marc Detection of peptidoglycans by NOD proteins Journal Article Trends Cell Biol., 13 (12), pp. 610–614, 2003, ISSN: 0962-8924. @article{royet_detection_2003, title = {Detection of peptidoglycans by NOD proteins}, author = { Julien Royet and Jean-Marc Reichhart}, issn = {0962-8924}, year = {2003}, date = {2003-12-01}, journal = {Trends Cell Biol.}, volume = {13}, number = {12}, pages = {610--614}, abstract = {Mechanisms of innate immune defense are based on the recognition of invariant microbial molecular patterns by specific receptors, followed by the activation of signaling pathways and the expression of effector molecules that will defeat the invading microorganism. Two recent reports add to the growing list of these pattern-recognition receptors by showing that the intracellular nucleotide-binding oligomerization domain 1 (NOD1) protein recognizes a diaminopimelate-containing muropeptide, a cell-wall component of Gram-negative bacteria.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Mechanisms of innate immune defense are based on the recognition of invariant microbial molecular patterns by specific receptors, followed by the activation of signaling pathways and the expression of effector molecules that will defeat the invading microorganism. Two recent reports add to the growing list of these pattern-recognition receptors by showing that the intracellular nucleotide-binding oligomerization domain 1 (NOD1) protein recognizes a diaminopimelate-containing muropeptide, a cell-wall component of Gram-negative bacteria. |
| 66. | Goto, Akira; Blandin, Stéphanie A; Royet, Julien; Reichhart, Jean-Marc; Levashina, Elena A Silencing of Toll pathway components by direct injection of double-stranded RNA into Drosophila adult flies Journal Article Nucleic Acids Res., 31 (22), pp. 6619–6623, 2003, ISSN: 1362-4962. @article{goto_silencing_2003, title = {Silencing of Toll pathway components by direct injection of double-stranded RNA into Drosophila adult flies}, author = { Akira Goto and Stéphanie A. Blandin and Julien Royet and Jean-Marc Reichhart and Elena A. Levashina}, issn = {1362-4962}, year = {2003}, date = {2003-11-01}, journal = {Nucleic Acids Res.}, volume = {31}, number = {22}, pages = {6619--6623}, abstract = {Double-stranded RNA (dsRNA) gene interference is an efficient method to silence gene expression in a sequence-specific manner. Here we show that the direct injection of dsRNA can be used in adult Drosophila flies to disrupt function of endogenous genes in vivo. As a proof of principle, we have used this method to silence components of a major signaling cascade, the Toll pathway, which controls fruit fly resistance to fungal and Gram-positive bacterial infections. We demonstrate that the knockout is efficient only if dsRNA is injected in 4- or more day-old flies and that it lasts for at least 1 week. Furthermore, we report dsRNA-based epistatic gene analysis via injection of a mixture of two dsRNAs and propose that injection of dsRNA represents a powerful method for rapid functional analysis of genes in Drosophila melanogaster adults, particularly of those whose mutations are lethal during development.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Double-stranded RNA (dsRNA) gene interference is an efficient method to silence gene expression in a sequence-specific manner. Here we show that the direct injection of dsRNA can be used in adult Drosophila flies to disrupt function of endogenous genes in vivo. As a proof of principle, we have used this method to silence components of a major signaling cascade, the Toll pathway, which controls fruit fly resistance to fungal and Gram-positive bacterial infections. We demonstrate that the knockout is efficient only if dsRNA is injected in 4- or more day-old flies and that it lasts for at least 1 week. Furthermore, we report dsRNA-based epistatic gene analysis via injection of a mixture of two dsRNAs and propose that injection of dsRNA represents a powerful method for rapid functional analysis of genes in Drosophila melanogaster adults, particularly of those whose mutations are lethal during development. |
| 65. | Green, Clare; Brown, Gemma; Dafforn, Timothy R; Reichhart, Jean-Marc; Morley, Terri; Lomas, David A; Gubb, David Drosophila necrotic mutations mirror disease-associated variants of human serpins Journal Article Development, 130 (7), pp. 1473–1478, 2003, ISSN: 0950-1991. @article{green_drosophila_2003, title = {Drosophila necrotic mutations mirror disease-associated variants of human serpins}, author = { Clare Green and Gemma Brown and Timothy R. Dafforn and Jean-Marc Reichhart and Terri Morley and David A. Lomas and David Gubb}, issn = {0950-1991}, year = {2003}, date = {2003-04-01}, journal = {Development}, volume = {130}, number = {7}, pages = {1473--1478}, abstract = {Polymerization of members of the serpin superfamily underlies diseases as diverse as cirrhosis, angioedema, thrombosis and dementia. The Drosophila serpin Necrotic controls the innate immune response and is homologous to human alpha(1)-antitrypsin. We show that necrotic mutations that are identical to the Z-deficiency variant of alpha(1)-antitrypsin form urea-stable polymers in vivo. These necrotic mutations are temperature sensitive, which is in keeping with the temperature-dependent polymerization of serpins in vitro and the role of childhood fevers in exacerbating liver disease in Z alpha-antitrypsin deficiency. In addition, we identify two nec mutations homologous to an antithrombin point mutation that is responsible for neonatal thrombosis. Transgenic flies carrying an StextgreaterF amino-acid substitution equivalent to that found in Siiyama-variant antitrypsin (nec(StextgreaterF.UAS)) fail to complement nec-null mutations and demonstrate a dominant temperature-dependent inactivation of the wild-type nec allele. Taken together, these data establish Drosophila as a powerful system to study serpin polymerization in vivo.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Polymerization of members of the serpin superfamily underlies diseases as diverse as cirrhosis, angioedema, thrombosis and dementia. The Drosophila serpin Necrotic controls the innate immune response and is homologous to human alpha(1)-antitrypsin. We show that necrotic mutations that are identical to the Z-deficiency variant of alpha(1)-antitrypsin form urea-stable polymers in vivo. These necrotic mutations are temperature sensitive, which is in keeping with the temperature-dependent polymerization of serpins in vitro and the role of childhood fevers in exacerbating liver disease in Z alpha-antitrypsin deficiency. In addition, we identify two nec mutations homologous to an antithrombin point mutation that is responsible for neonatal thrombosis. Transgenic flies carrying an StextgreaterF amino-acid substitution equivalent to that found in Siiyama-variant antitrypsin (nec(StextgreaterF.UAS)) fail to complement nec-null mutations and demonstrate a dominant temperature-dependent inactivation of the wild-type nec allele. Taken together, these data establish Drosophila as a powerful system to study serpin polymerization in vivo. |
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Journal Articles |
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| 64. | Ligoxygakis, Petros; Pelte, Nadège ; Ji, Chuanyi ; Leclerc, Vincent ; Duvic, Bernard ; Belvin, Marcia ; Jiang, Haobo ; Hoffmann, Jules A; Reichhart, Jean-Marc A serpin mutant links Toll activation to melanization in the host defence of Drosophila Journal Article EMBO J., 21 (23), pp. 6330–6337, 2002, ISSN: 0261-4189. @article{ligoxygakis_serpin_2002, title = {A serpin mutant links Toll activation to melanization in the host defence of Drosophila}, author = { Petros Ligoxygakis and Nadège Pelte and Chuanyi Ji and Vincent Leclerc and Bernard Duvic and Marcia Belvin and Haobo Jiang and Jules A. Hoffmann and Jean-Marc Reichhart}, issn = {0261-4189}, year = {2002}, date = {2002-12-01}, journal = {EMBO J.}, volume = {21}, number = {23}, pages = {6330--6337}, abstract = {A prominent response during the Drosophila host defence is the induction of proteolytic cascades, some of which lead to localized melanization of pathogen surfaces, while others activate one of the major players in the systemic antimicrobial response, the Toll pathway. Despite the fact that gain-of-function mutations in the Toll receptor gene result in melanization, a clear link between Toll activation and the melanization reaction has not been firmly established. Here, we present evidence for the coordination of hemolymph-borne melanization with activation of the Toll pathway in the Drosophila host defence. The melanization reaction requires Toll pathway activation and depends on the removal of the Drosophila serine protease inhibitor Serpin27A. Flies deficient for this serpin exhibit spontaneous melanization in larvae and adults. Microbial challenge induces its removal from the hemolymph through Toll-dependent transcription of an acute phase immune reaction component.}, keywords = {}, pubstate = {published}, tppubtype = {article} } A prominent response during the Drosophila host defence is the induction of proteolytic cascades, some of which lead to localized melanization of pathogen surfaces, while others activate one of the major players in the systemic antimicrobial response, the Toll pathway. Despite the fact that gain-of-function mutations in the Toll receptor gene result in melanization, a clear link between Toll activation and the melanization reaction has not been firmly established. Here, we present evidence for the coordination of hemolymph-borne melanization with activation of the Toll pathway in the Drosophila host defence. The melanization reaction requires Toll pathway activation and depends on the removal of the Drosophila serine protease inhibitor Serpin27A. Flies deficient for this serpin exhibit spontaneous melanization in larvae and adults. Microbial challenge induces its removal from the hemolymph through Toll-dependent transcription of an acute phase immune reaction component. |
Topics
Actuality and last Publications
- Hyd ubiquitinates the NF-κB co-factor Akirin to activate an effective immune response in Drosophila
- Quorum-sensing regulator RhlR but not its autoinducer RhlI enables Pseudomonas to evade opsonization
- A mechanism for detecting microbial virulence in Drosophila
- Global Experts Recruitment Chinese Program
- Hyd ubiquitinates the NF-κB co-factor Akirin to activate an effective immune response in Drosophila
- Post-doctoral Position: Antiviral innate immunity in Drosophila
- Awards of medals of honor 2016 in the Alsace delegation of the CNRS
- Communication: Enterocyte Purge and Rapid Recovery Is a Resilience Reaction of the Gut Epithelium to Pore-Forming Toxin Attack
- New insectarium
- Kids Universities 2016