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2014 |
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 Article de journal EMBO J., 33 (20), p. 2349–2362, 2014, ISSN: 1460-2075. Résumé | Liens | BibTeX | Étiquettes: Animals, bioinformatic, Cell Cycle Proteins, Chromatin Assembly and Disassembly, chromatin remodeling, DNA-Binding Proteins, Female, Genetic, Immunity, Innate, Innate immune response, M3i, Male, matt, Mutation, NF-kappa B, NF‐κB, Promoter Regions, proteomics, reichhart, Trans-Activators, Transcription Factors, Transcriptional Activation, Two-Hybrid System Techniques @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 = {Animals, bioinformatic, Cell Cycle Proteins, Chromatin Assembly and Disassembly, chromatin remodeling, DNA-Binding Proteins, Female, Genetic, Immunity, Innate, Innate immune response, M3i, Male, matt, Mutation, NF-kappa B, NF‐κB, Promoter Regions, proteomics, reichhart, Trans-Activators, Transcription Factors, Transcriptional Activation, Two-Hybrid System Techniques}, 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. |
Goto, Akira; Fukuyama, Hidehiro; Imler, Jean-Luc; Hoffmann, Jules A The chromatin regulator DMAP1 modulates activity of the nuclear factor B (NF-B) transcription factor Relish in the Drosophila innate immune response Article de journal The Journal of Biological Chemistry, 289 (30), p. 20470–20476, 2014, ISSN: 1083-351X. Résumé | Liens | BibTeX | Étiquettes: Animals, Cell Line, Chromatin Assembly and Disassembly, Epistasis, Escherichia coli, Escherichia coli Infections, Genetic, hoffmann, imler, Immunity, Innate, M3i, NF-kappa B, Repressor Proteins, Signal Transduction, Transcription Factors @article{goto_chromatin_2014, title = {The chromatin regulator DMAP1 modulates activity of the nuclear factor B (NF-B) transcription factor Relish in the Drosophila innate immune response}, author = {Akira Goto and Hidehiro Fukuyama and Jean-Luc Imler and Jules A Hoffmann}, doi = {10.1074/jbc.C114.553719}, issn = {1083-351X}, year = {2014}, date = {2014-07-01}, journal = {The Journal of Biological Chemistry}, volume = {289}, number = {30}, pages = {20470--20476}, abstract = {The host defense of the model organism Drosophila is under the control of two major signaling cascades controlling transcription factors of the NF-B family, the Toll and the immune deficiency (IMD) pathways. The latter shares extensive similarities with the mammalian TNF-R pathway and was initially discovered for its role in anti-Gram-negative bacterial reactions. A previous interactome study from this laboratory reported that an unexpectedly large number of proteins are binding to the canonical components of the IMD pathway. Here, we focus on DNA methyltransferase-associated protein 1 (DMAP1), which this study identified as an interactant of Relish, a Drosophila transcription factor reminiscent of the mammalian p105 NF-B protein. We show that silencing of DMAP1 expression both in S2 cells and in flies results in a significant reduction of Escherichia coli-induced expression of antimicrobial peptides. Epistatic analysis indicates that DMAP1 acts in parallel or downstream of Relish. Co-immunoprecipitation experiments further reveal that, in addition to Relish, DMAP1 also interacts with Akirin and the Brahma-associated protein 55 kDa (BAP55). Taken together, these results reveal that DMAP1 is a novel nuclear modulator of the IMD pathway, possibly acting at the level of chromatin remodeling.}, keywords = {Animals, Cell Line, Chromatin Assembly and Disassembly, Epistasis, Escherichia coli, Escherichia coli Infections, Genetic, hoffmann, imler, Immunity, Innate, M3i, NF-kappa B, Repressor Proteins, Signal Transduction, Transcription Factors}, pubstate = {published}, tppubtype = {article} } The host defense of the model organism Drosophila is under the control of two major signaling cascades controlling transcription factors of the NF-B family, the Toll and the immune deficiency (IMD) pathways. The latter shares extensive similarities with the mammalian TNF-R pathway and was initially discovered for its role in anti-Gram-negative bacterial reactions. A previous interactome study from this laboratory reported that an unexpectedly large number of proteins are binding to the canonical components of the IMD pathway. Here, we focus on DNA methyltransferase-associated protein 1 (DMAP1), which this study identified as an interactant of Relish, a Drosophila transcription factor reminiscent of the mammalian p105 NF-B protein. We show that silencing of DMAP1 expression both in S2 cells and in flies results in a significant reduction of Escherichia coli-induced expression of antimicrobial peptides. Epistatic analysis indicates that DMAP1 acts in parallel or downstream of Relish. Co-immunoprecipitation experiments further reveal that, in addition to Relish, DMAP1 also interacts with Akirin and the Brahma-associated protein 55 kDa (BAP55). Taken together, these results reveal that DMAP1 is a novel nuclear modulator of the IMD pathway, possibly acting at the level of chromatin remodeling. |
2011 |
Lee, Kwang-Zin; Ferrandon, Dominique Negative regulation of immune responses on the fly Article de journal EMBO J., 30 (6), p. 988–990, 2011, ISSN: 1460-2075. Liens | BibTeX | Étiquettes: *Gene Expression Regulation, *Homeostasis, Animals, bacteria, Bacteria/*immunology, Biological, Drosophila melanogaster/*immunology, Drosophila Proteins/biosynthesis/metabolism, ferrandon, Gene Expression Regulation, Homeostasis, M3i, Mitogen-Activated Protein Kinases, Mitogen-Activated Protein Kinases/metabolism, Models, NF-kappa B, NF-kappa B/metabolism, ras Proteins, ras Proteins/metabolism, Receptor Protein-Tyrosine Kinases, Receptor Protein-Tyrosine Kinases/metabolism @article{lee_negative_2011b, title = {Negative regulation of immune responses on the fly}, author = {Kwang-Zin Lee and Dominique Ferrandon}, doi = {10.1038/emboj.2011.47}, issn = {1460-2075}, year = {2011}, date = {2011-01-01}, journal = {EMBO J.}, volume = {30}, number = {6}, pages = {988--990}, keywords = {*Gene Expression Regulation, *Homeostasis, Animals, bacteria, Bacteria/*immunology, Biological, Drosophila melanogaster/*immunology, Drosophila Proteins/biosynthesis/metabolism, ferrandon, Gene Expression Regulation, Homeostasis, M3i, Mitogen-Activated Protein Kinases, Mitogen-Activated Protein Kinases/metabolism, Models, NF-kappa B, NF-kappa B/metabolism, ras Proteins, ras Proteins/metabolism, Receptor Protein-Tyrosine Kinases, Receptor Protein-Tyrosine Kinases/metabolism}, pubstate = {published}, tppubtype = {article} } |
2010 |
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 Article de journal Mol. Cell, 37 (2), p. 172–182, 2010, ISSN: 1097-4164. Résumé | Liens | BibTeX | Étiquettes: Alleles, Amino Acid Motifs, Animals, Biological, Caspases, Inhibitor of Apoptosis Proteins, M3i, MAP Kinase Kinase Kinases, Models, NF-kappa B, reichhart, Sequence Alignment, Signal Transduction, Ubiquitin-Protein Ligases, Ubiquitination @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 = {Alleles, Amino Acid Motifs, Animals, Biological, Caspases, Inhibitor of Apoptosis Proteins, M3i, MAP Kinase Kinase Kinases, Models, NF-kappa B, reichhart, Sequence Alignment, Signal Transduction, Ubiquitin-Protein Ligases, Ubiquitination}, 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 |
Hetru, Charles; Hoffmann, Jules A NF-kappaB in the immune response of Drosophila Article de journal Cold Spring Harb Perspect Biol, 1 (6), p. a000232, 2009, ISSN: 1943-0264. Résumé | Liens | BibTeX | Étiquettes: Animals, bacteria, Fungi, Gene Expression Regulation, hoffmann, M3i, NF-kappa B @article{hetru_nf-kappab_2009, title = {NF-kappaB in the immune response of Drosophila}, author = {Charles Hetru and Jules A Hoffmann}, doi = {10.1101/cshperspect.a000232}, issn = {1943-0264}, year = {2009}, date = {2009-12-01}, journal = {Cold Spring Harb Perspect Biol}, volume = {1}, number = {6}, pages = {a000232}, abstract = {The nuclear factor kappaB (NF-kappaB) pathways play a major role in Drosophila host defense. Two recognition and signaling cascades control this immune response. The Toll pathway is activated by Gram-positive bacteria and by fungi, whereas the immune deficiency (Imd) pathway responds to Gram-negative bacterial infection. The basic mechanisms of recognition of these various types of microbial infections by the adult fly are now globally understood. Even though some elements are missing in the intracellular pathways, numerous proteins and interactions have been identified. In this article, we present a general picture of the immune functions of NF-kappaB in Drosophila with all the partners involved in recognition and in the signaling cascades.}, keywords = {Animals, bacteria, Fungi, Gene Expression Regulation, hoffmann, M3i, NF-kappa B}, pubstate = {published}, tppubtype = {article} } The nuclear factor kappaB (NF-kappaB) pathways play a major role in Drosophila host defense. Two recognition and signaling cascades control this immune response. The Toll pathway is activated by Gram-positive bacteria and by fungi, whereas the immune deficiency (Imd) pathway responds to Gram-negative bacterial infection. The basic mechanisms of recognition of these various types of microbial infections by the adult fly are now globally understood. Even though some elements are missing in the intracellular pathways, numerous proteins and interactions have been identified. In this article, we present a general picture of the immune functions of NF-kappaB in Drosophila with all the partners involved in recognition and in the signaling cascades. |
2008 |
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 Article de journal Nat. Immunol., 9 (1), p. 97–104, 2008, ISSN: 1529-2916. Résumé | Liens | BibTeX | Étiquettes: Animals, Cell Line, Embryo, Fibroblasts, hoffmann, Humans, Immunity, Innate, Interleukin-1beta, M3i, Mammalian, Mice, NF-kappa B, Nuclear Proteins, Proteins, reichhart, Signal Transduction, Toll-Like Receptors, transgenic, Tumor Necrosis Factor-alpha @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 = {Animals, Cell Line, Embryo, Fibroblasts, hoffmann, Humans, Immunity, Innate, Interleukin-1beta, M3i, Mammalian, Mice, NF-kappa B, Nuclear Proteins, Proteins, reichhart, Signal Transduction, Toll-Like Receptors, transgenic, Tumor Necrosis Factor-alpha}, 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. |
2006 |
Frolet, Cécile; Thoma, Martine; Blandin, Stéphanie A; Hoffmann, Jules A; Levashina, Elena A Boosting NF-kappaB-dependent basal immunity of Anopheles gambiae aborts development of Plasmodium berghei Article de journal Immunity, 25 (4), p. 677–685, 2006, ISSN: 1074-7613. Résumé | Liens | BibTeX | Étiquettes: Animals, Anopheles gambiae, blandin, Gene Expression, Gene Expression Regulation, Genes, hoffmann, Immunity, Insect, M3i, NF-kappa B, Plasmodium berghei, telomerase @article{frolet_boosting_2006, title = {Boosting NF-kappaB-dependent basal immunity of Anopheles gambiae aborts development of Plasmodium berghei}, author = {Cécile Frolet and Martine Thoma and Stéphanie A Blandin and Jules A Hoffmann and Elena A Levashina}, url = {http://www.ncbi.nlm.nih.gov/pubmed/17045818}, doi = {10.1016/j.immuni.2006.08.019}, issn = {1074-7613}, year = {2006}, date = {2006-10-01}, journal = {Immunity}, volume = {25}, number = {4}, pages = {677--685}, abstract = {Anopheles gambiae, the major vector for the protozoan malaria parasite Plasmodium falciparum, mounts powerful antiparasitic responses that cause marked parasite loss during midgut invasion. Here, we showed that these antiparasitic defenses were composed of pre- and postinvasion phases and that the preinvasion phase was predominantly regulated by Rel1 and Rel2 members of the NF-kappaB transcription factors. Concurrent silencing of Rel1 and Rel2 decreased the basal expression of the major antiparasitic genes TEP1 and LRIM1 and abolished resistance of Anopheles to the rodent malaria parasite P. berghei. Conversely, depletion of a negative regulator of Rel1, Cactus, prior to infection, enhanced the basal expression of TEP1 and of other immune factors and completely prevented parasite development. Our findings uncover the crucial role of the preinvasion defense in the elimination of parasites, which is at least in part based on circulating blood molecules.}, keywords = {Animals, Anopheles gambiae, blandin, Gene Expression, Gene Expression Regulation, Genes, hoffmann, Immunity, Insect, M3i, NF-kappa B, Plasmodium berghei, telomerase}, pubstate = {published}, tppubtype = {article} } Anopheles gambiae, the major vector for the protozoan malaria parasite Plasmodium falciparum, mounts powerful antiparasitic responses that cause marked parasite loss during midgut invasion. Here, we showed that these antiparasitic defenses were composed of pre- and postinvasion phases and that the preinvasion phase was predominantly regulated by Rel1 and Rel2 members of the NF-kappaB transcription factors. Concurrent silencing of Rel1 and Rel2 decreased the basal expression of the major antiparasitic genes TEP1 and LRIM1 and abolished resistance of Anopheles to the rodent malaria parasite P. berghei. Conversely, depletion of a negative regulator of Rel1, Cactus, prior to infection, enhanced the basal expression of TEP1 and of other immune factors and completely prevented parasite development. Our findings uncover the crucial role of the preinvasion defense in the elimination of parasites, which is at least in part based on circulating blood molecules. |
2000 |
Imler, Jean-Luc; Hoffmann, Jules A Toll and Toll-like proteins: an ancient family of receptors signaling infection Article de journal Reviews in Immunogenetics, 2 (3), p. 294–304, 2000, ISSN: 1398-1714. Résumé | BibTeX | Étiquettes: Adaptor Proteins, Animals, Antigens, Autoantigens, CD14, Cell Adhesion Molecules, Cell Surface, Differentiation, DNA-Binding Proteins, Gene Expression Regulation, hoffmann, I-kappa B Proteins, imler, Immunity, Immunologic, infection, Innate, Insect Proteins, Interleukin-1 Receptor-Associated Kinases, Knockout, Larva, Lipopolysaccharides, M3i, Mammals, MAP Kinase Signaling System, Membrane Glycoproteins, Membrane Proteins, Mice, Multigene Family, Myeloid Differentiation Factor 88, NF-kappa B, peptidoglycan, Phosphorylation, Post-Translational, Protein Kinases, Protein Processing, Protein Structure, Receptors, Recombinant Fusion Proteins, Signal Transducing, Signal Transduction, Teichoic Acids, Tertiary, Toll-Like Receptor 4, Toll-Like Receptor 5, Toll-Like Receptor 6, Toll-Like Receptor 9, Toll-Like Receptors, Ubiquitins @article{imler_toll_2000, title = {Toll and Toll-like proteins: an ancient family of receptors signaling infection}, author = {Jean-Luc Imler and Jules A Hoffmann}, issn = {1398-1714}, year = {2000}, date = {2000-01-01}, journal = {Reviews in Immunogenetics}, volume = {2}, number = {3}, pages = {294--304}, abstract = {Innate immunity is the first-line host defense of multicellular organisms that rapidly operates to limit infection upon exposure to microbes. It involves intracellular signaling pathways in the fruit-fly Drosophila and in mammals that show striking similarities. Recent genetic and biochemical data have revealed, in particular, that proteins of the Toll family play a critical role in the immediate response to infection. We review here the recent developments on the structural and functional characterization of this evolutionary ancient and important family of proteins, which can function as cytokine receptors (Toll in Drosophila) or pattern recognition receptors (TLR4 in mammals) and activate similar, albeit non identical signal transduction pathways, in flies and mammals.}, keywords = {Adaptor Proteins, Animals, Antigens, Autoantigens, CD14, Cell Adhesion Molecules, Cell Surface, Differentiation, DNA-Binding Proteins, Gene Expression Regulation, hoffmann, I-kappa B Proteins, imler, Immunity, Immunologic, infection, Innate, Insect Proteins, Interleukin-1 Receptor-Associated Kinases, Knockout, Larva, Lipopolysaccharides, M3i, Mammals, MAP Kinase Signaling System, Membrane Glycoproteins, Membrane Proteins, Mice, Multigene Family, Myeloid Differentiation Factor 88, NF-kappa B, peptidoglycan, Phosphorylation, Post-Translational, Protein Kinases, Protein Processing, Protein Structure, Receptors, Recombinant Fusion Proteins, Signal Transducing, Signal Transduction, Teichoic Acids, Tertiary, Toll-Like Receptor 4, Toll-Like Receptor 5, Toll-Like Receptor 6, Toll-Like Receptor 9, Toll-Like Receptors, Ubiquitins}, pubstate = {published}, tppubtype = {article} } Innate immunity is the first-line host defense of multicellular organisms that rapidly operates to limit infection upon exposure to microbes. It involves intracellular signaling pathways in the fruit-fly Drosophila and in mammals that show striking similarities. Recent genetic and biochemical data have revealed, in particular, that proteins of the Toll family play a critical role in the immediate response to infection. We review here the recent developments on the structural and functional characterization of this evolutionary ancient and important family of proteins, which can function as cytokine receptors (Toll in Drosophila) or pattern recognition receptors (TLR4 in mammals) and activate similar, albeit non identical signal transduction pathways, in flies and mammals. |
1996 |
Barillas-Mury, Carolina; Charlesworth, A; Gross, I; Richman, A; Hoffmann, Jules A; Kafatos, Fotis C Immune factor Gambif1, a new rel family member from the human malaria vector, Anopheles gambiae Article de journal EMBO J., 15 (17), p. 4691–4701, 1996, ISSN: 0261-4189. Résumé | BibTeX | Étiquettes: Amino Acid, Animals, Anopheles, Base Sequence, Biological Transport, Cell Nucleus, Cells, Complementary, Cultured, DNA, DNA-Binding Proteins, hoffmann, Insect Proteins, Insect Vectors, M3i, NF-kappa B, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-rel, Sequence Homology, Trans-Activators, Transcriptional Activation @article{barillas-mury_immune_1996, title = {Immune factor Gambif1, a new rel family member from the human malaria vector, Anopheles gambiae}, author = {Carolina Barillas-Mury and A Charlesworth and I Gross and A Richman and Jules A Hoffmann and Fotis C Kafatos}, issn = {0261-4189}, year = {1996}, date = {1996-09-01}, journal = {EMBO J.}, volume = {15}, number = {17}, pages = {4691--4701}, abstract = {A novel rel family member, Gambif1 (gambiae immune factor 1), has been cloned from the human malaria vector, Anopheles gambiae, and shown to be most similar to Drosophila Dorsal and Dif. Gambif1 protein is translocated to the nucleus in fat body cells in response to bacterial challenge, although the mRNA is present at low levels at all developmental stages and is not induced by infection. DNA binding activity to the kappaB-like sites in the A.gambiae Defensin and the Drosophila Diptericin and Cecropin promoters is also induced in larval nuclear extracts following infection. Gambif1 has the ability to bind to kappaB-like sites in vitro. Co-transfection assays in Drosophila mbn-2 cells show that Gambif1 can activate transcription by interacting with the Drosophila Diptericin regulatory elements, but is not functionally equivalent to Dorsal in this assay. Gambif1 protein translocation to the nucleus and the appearance of kappaB-like DNA binding activity can serve as molecular markers of activation of the immune system and open up the possibility of studying the role of defence reactions in determining mosquito susceptibility/refractoriness to malaria infection.}, keywords = {Amino Acid, Animals, Anopheles, Base Sequence, Biological Transport, Cell Nucleus, Cells, Complementary, Cultured, DNA, DNA-Binding Proteins, hoffmann, Insect Proteins, Insect Vectors, M3i, NF-kappa B, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-rel, Sequence Homology, Trans-Activators, Transcriptional Activation}, pubstate = {published}, tppubtype = {article} } A novel rel family member, Gambif1 (gambiae immune factor 1), has been cloned from the human malaria vector, Anopheles gambiae, and shown to be most similar to Drosophila Dorsal and Dif. Gambif1 protein is translocated to the nucleus in fat body cells in response to bacterial challenge, although the mRNA is present at low levels at all developmental stages and is not induced by infection. DNA binding activity to the kappaB-like sites in the A.gambiae Defensin and the Drosophila Diptericin and Cecropin promoters is also induced in larval nuclear extracts following infection. Gambif1 has the ability to bind to kappaB-like sites in vitro. Co-transfection assays in Drosophila mbn-2 cells show that Gambif1 can activate transcription by interacting with the Drosophila Diptericin regulatory elements, but is not functionally equivalent to Dorsal in this assay. Gambif1 protein translocation to the nucleus and the appearance of kappaB-like DNA binding activity can serve as molecular markers of activation of the immune system and open up the possibility of studying the role of defence reactions in determining mosquito susceptibility/refractoriness to malaria infection. |
Gross, I; Georgel, Philippe; Kappler, Christine; Reichhart, Jean-Marc; Hoffmann, Jules A Drosophila immunity: a comparative analysis of the Rel proteins dorsal and Dif in the induction of the genes encoding diptericin and cecropin Article de journal Nucleic Acids Res., 24 (7), p. 1238–1245, 1996, ISSN: 0305-1048. Résumé | BibTeX | Étiquettes: Animals, Antimicrobial Cationic Peptides, Base Sequence, DNA Primers, DNA-Binding Proteins, Gene Expression Regulation, Genetic, hoffmann, Insect Hormones, Insect Proteins, M3i, NF-kappa B, Nuclear Proteins, Peptides, Phosphoproteins, reichhart, Transcription, Transcription Factors, Transcriptional Activation @article{gross_drosophila_1996, title = {Drosophila immunity: a comparative analysis of the Rel proteins dorsal and Dif in the induction of the genes encoding diptericin and cecropin}, author = {I Gross and Philippe Georgel and Christine Kappler and Jean-Marc Reichhart and Jules A Hoffmann}, issn = {0305-1048}, year = {1996}, date = {1996-04-01}, journal = {Nucleic Acids Res.}, volume = {24}, number = {7}, pages = {1238--1245}, abstract = {In Drosophila, bacterial challenge induces the rapid transcription of several genes encoding potent antibacterial peptides. The upstream sequences of the diptericin and cecropin Al genes, which have been investigated in detail, contain two, respectively one sequence element homologous to the binding site of the mammalian nuclear factor kappaB. These elements have been shown to be mandatory for immune-induced transcription of both genes. Functional studies have shown that these kappaB-related elements can be the target for the Drosophila Rel proteins dorsal and Dif. Here we present a comparative analysis of the transactivating capacities of these proteins on reporter genes fused to either the diptericin or the cecropin kappaB-related motifs. We conclude from our results: (i) the kappaB motifs of the diptericin and cecropin genes are not functionally equivalent; (ii) the dorsal and Dif proteins have distinct DNA-binding characteristics; (iii) dorsal and Dif can heterodimerize in vitro; (iv) mutants containing no copies of dorsal and a single copy of Dif retain their full capacity to express the diptericin and cecropin genes in response to challenge.}, keywords = {Animals, Antimicrobial Cationic Peptides, Base Sequence, DNA Primers, DNA-Binding Proteins, Gene Expression Regulation, Genetic, hoffmann, Insect Hormones, Insect Proteins, M3i, NF-kappa B, Nuclear Proteins, Peptides, Phosphoproteins, reichhart, Transcription, Transcription Factors, Transcriptional Activation}, pubstate = {published}, tppubtype = {article} } In Drosophila, bacterial challenge induces the rapid transcription of several genes encoding potent antibacterial peptides. The upstream sequences of the diptericin and cecropin Al genes, which have been investigated in detail, contain two, respectively one sequence element homologous to the binding site of the mammalian nuclear factor kappaB. These elements have been shown to be mandatory for immune-induced transcription of both genes. Functional studies have shown that these kappaB-related elements can be the target for the Drosophila Rel proteins dorsal and Dif. Here we present a comparative analysis of the transactivating capacities of these proteins on reporter genes fused to either the diptericin or the cecropin kappaB-related motifs. We conclude from our results: (i) the kappaB motifs of the diptericin and cecropin genes are not functionally equivalent; (ii) the dorsal and Dif proteins have distinct DNA-binding characteristics; (iii) dorsal and Dif can heterodimerize in vitro; (iv) mutants containing no copies of dorsal and a single copy of Dif retain their full capacity to express the diptericin and cecropin genes in response to challenge. |
Lemaitre, Bruno; Nicolas, E; Michaut, Lydia; Reichhart, Jean-Marc; Hoffmann, Jules A The dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in Drosophila adults Article de journal Cell, 86 (6), p. 973–983, 1996, ISSN: 0092-8674. Résumé | BibTeX | Étiquettes: Animals, Antifungal Agents, Cell Surface, DNA-Binding Proteins, Fungi, Gene Expression, Genes, hoffmann, Insect, Insect Hormones, Insect Proteins, M3i, Membrane Glycoproteins, MHC Class II, Mutation, Mycoses, NF-kappa B, Phosphoproteins, Proteins, Receptors, reichhart, Signal Transduction, Toll-Like Receptors @article{lemaitre_dorsoventral_1996, title = {The dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in Drosophila adults}, author = {Bruno Lemaitre and E Nicolas and Lydia Michaut and Jean-Marc Reichhart and Jules A Hoffmann}, issn = {0092-8674}, year = {1996}, date = {1996-01-01}, journal = {Cell}, volume = {86}, number = {6}, pages = {973--983}, 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, 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 = {Animals, Antifungal Agents, Cell Surface, DNA-Binding Proteins, Fungi, Gene Expression, Genes, hoffmann, Insect, Insect Hormones, Insect Proteins, M3i, Membrane Glycoproteins, MHC Class II, Mutation, Mycoses, NF-kappa B, Phosphoproteins, Proteins, Receptors, reichhart, Signal Transduction, Toll-Like Receptors}, 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, 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. |
1995 |
Georgel, Philippe; Kappler, Christine; Langley, E; Gross, I; Nicolas, E; Reichhart, Jean-Marc; Hoffmann, Jules A Drosophila immunity. A sequence homologous to mammalian interferon consensus response element enhances the activity of the diptericin promoter Article de journal Nucleic Acids Res., 23 (7), p. 1140–1145, 1995, ISSN: 0305-1048. Résumé | BibTeX | Étiquettes: Animals, Base Sequence, CCAAT-Enhancer-Binding Proteins, DNA, DNA-Binding Proteins, Genes, Genetic, hoffmann, Immunity, Insect, Insect Hormones, Insect Proteins, interferons, Lipopolysaccharides, M3i, NF-kappa B, Nuclear Proteins, Plasmids, Promoter Regions, reichhart, Up-Regulation @article{georgel_drosophila_1995, title = {Drosophila immunity. A sequence homologous to mammalian interferon consensus response element enhances the activity of the diptericin promoter}, author = {Philippe Georgel and Christine Kappler and E Langley and I Gross and E Nicolas and Jean-Marc Reichhart and Jules A Hoffmann}, issn = {0305-1048}, year = {1995}, date = {1995-04-01}, journal = {Nucleic Acids Res.}, volume = {23}, number = {7}, pages = {1140--1145}, abstract = {Bacterial challenge of larvae or adults of Drosophila induces the rapid transcription of several genes encoding antibacterial peptides with a large spectrum of activity. One of these peptides, the 82-residue anti-gram negative diptericin, is encoded by a single intronless gene and we are investigating the control of expression of this gene. Previous studies using both transgenic experiments and footprint analysis have highlighted the role in the induction of this gene of a 30 nucleotide region which contains three partially overlapping motifs with sequence homology to mammalian NF-kappa B and NF-IL6 response elements and to the GAAANN sequence present in the interferon consensus response elements of some mammalian interferon-induced genes. We now show that the latter sequence binds in immune responsive tissues (fat body, blood cells) of Drosophila a approximately 45 kDa polypeptide which cross-reacts with a polyserum directed against mammalian interferon Regulatory Factor-I. Using a transfection assay of Drosophila tumorous blood cells, we show that the GAAANN sequence positively regulates the activity of the diptericin promoter. We propose that this motif cooperatively interacts with the other response elements in the regulation of the diptericin gene expression.}, keywords = {Animals, Base Sequence, CCAAT-Enhancer-Binding Proteins, DNA, DNA-Binding Proteins, Genes, Genetic, hoffmann, Immunity, Insect, Insect Hormones, Insect Proteins, interferons, Lipopolysaccharides, M3i, NF-kappa B, Nuclear Proteins, Plasmids, Promoter Regions, reichhart, Up-Regulation}, pubstate = {published}, tppubtype = {article} } Bacterial challenge of larvae or adults of Drosophila induces the rapid transcription of several genes encoding antibacterial peptides with a large spectrum of activity. One of these peptides, the 82-residue anti-gram negative diptericin, is encoded by a single intronless gene and we are investigating the control of expression of this gene. Previous studies using both transgenic experiments and footprint analysis have highlighted the role in the induction of this gene of a 30 nucleotide region which contains three partially overlapping motifs with sequence homology to mammalian NF-kappa B and NF-IL6 response elements and to the GAAANN sequence present in the interferon consensus response elements of some mammalian interferon-induced genes. We now show that the latter sequence binds in immune responsive tissues (fat body, blood cells) of Drosophila a approximately 45 kDa polypeptide which cross-reacts with a polyserum directed against mammalian interferon Regulatory Factor-I. Using a transfection assay of Drosophila tumorous blood cells, we show that the GAAANN sequence positively regulates the activity of the diptericin promoter. We propose that this motif cooperatively interacts with the other response elements in the regulation of the diptericin gene expression. |
1993 |
Georgel, Philippe; Meister, Marie; Kappler, Christine; Lemaitre, Bruno; Reichhart, Jean-Marc; Hoffmann, Jules A Insect immunity: the diptericin promoter contains multiple functional regulatory sequences homologous to mammalian acute-phase response elements Article de journal Biochem. Biophys. Res. Commun., 197 (2), p. 508–517, 1993, ISSN: 0006-291X. Résumé | Liens | BibTeX | Étiquettes: Acute-Phase Proteins, Animals, Anti-Infective Agents, Base Sequence, Cell Line, Deoxyribonuclease I, DNA-Binding Proteins, Genetic, hoffmann, Insect Hormones, Insect Proteins, Larva, M3i, Mammals, NF-kappa B, Nucleic Acid, Oligonucleotide Probes, Polymerase Chain Reaction, Promoter Regions, Regulatory Sequences, reichhart @article{georgel_insect_1993, title = {Insect immunity: the diptericin promoter contains multiple functional regulatory sequences homologous to mammalian acute-phase response elements}, author = {Philippe Georgel and Marie Meister and Christine Kappler and Bruno Lemaitre and Jean-Marc Reichhart and Jules A Hoffmann}, doi = {10.1006/bbrc.1993.2508}, issn = {0006-291X}, year = {1993}, date = {1993-12-01}, journal = {Biochem. Biophys. Res. Commun.}, volume = {197}, number = {2}, pages = {508--517}, abstract = {We are using the diptericin gene as a model system to study the control of expression of the genes encoding antibacterial peptides during the Drosophila immune reaction. In order to investigate the putative regulatory regions in the diptericin promoter, we performed DNaseI footprinting experiments combined with gel-shift assays in two inducible systems: the larval fat body and a tumorous Drosophila blood cell line. Our results confirm the importance of kappa B-like elements previously described in the immune response of insects and reveal for the first time the involvement of other regions containing sequences homologous to mammalian acute-phase response elements.}, keywords = {Acute-Phase Proteins, Animals, Anti-Infective Agents, Base Sequence, Cell Line, Deoxyribonuclease I, DNA-Binding Proteins, Genetic, hoffmann, Insect Hormones, Insect Proteins, Larva, M3i, Mammals, NF-kappa B, Nucleic Acid, Oligonucleotide Probes, Polymerase Chain Reaction, Promoter Regions, Regulatory Sequences, reichhart}, pubstate = {published}, tppubtype = {article} } We are using the diptericin gene as a model system to study the control of expression of the genes encoding antibacterial peptides during the Drosophila immune reaction. In order to investigate the putative regulatory regions in the diptericin promoter, we performed DNaseI footprinting experiments combined with gel-shift assays in two inducible systems: the larval fat body and a tumorous Drosophila blood cell line. Our results confirm the importance of kappa B-like elements previously described in the immune response of insects and reveal for the first time the involvement of other regions containing sequences homologous to mammalian acute-phase response elements. |
Kappler, Christine; Meister, Marie; Lagueux, Marie; Gateff, E; Hoffmann, Jules A; Reichhart, Jean-Marc Insect immunity. Two 17 bp repeats nesting a kappa B-related sequence confer inducibility to the diptericin gene and bind a polypeptide in bacteria-challenged Drosophila Article de journal EMBO J., 12 (4), p. 1561–1568, 1993, ISSN: 0261-4189. Résumé | BibTeX | Étiquettes: Animals, Anti-Bacterial Agents, Base Sequence, Cloning, Gene Expression Regulation, Genes, Genetic, Genetically Modified, hoffmann, Insect, Insect Hormones, Insect Proteins, Lipopolysaccharides, M3i, messenger, Molecular, NF-kappa B, Nucleic Acid, Oligodeoxyribonucleotides, Promoter Regions, Regulatory Sequences, reichhart, RNA, Transfection @article{kappler_insect_1993, title = {Insect immunity. Two 17 bp repeats nesting a kappa B-related sequence confer inducibility to the diptericin gene and bind a polypeptide in bacteria-challenged Drosophila}, author = {Christine Kappler and Marie Meister and Marie Lagueux and E Gateff and Jules A Hoffmann and Jean-Marc Reichhart}, issn = {0261-4189}, year = {1993}, date = {1993-04-01}, journal = {EMBO J.}, volume = {12}, number = {4}, pages = {1561--1568}, abstract = {The Drosophila diptericin gene codes for a 9 kDa antibacterial peptide and is rapidly and transiently expressed in larvae and adults after bacterial challenge. It is also induced in a tumorous Drosophila blood cell line by the addition of lipopolysaccharide (LPS). The promoter of this gene contains two 17 bp repeats located closely upstream of the TATA-box and harbouring a decameric kappa B-related sequence. This study reports that the replacement of the two 17 bp repeats by random sequences abolishes bacteria inducibility in transgenic fly lines. In transfected tumorous blood cells, the replacement of both or either of the 17 bp motifs reduces dramatically LPS inducibility, whereas multiple copies significantly increase the level of transcriptional activation by LPS challenge. A specific DNA-protein binding activity is evidenced in cytoplasmic and nuclear extracts of induced blood cells and fat body. It is absent in controls. It is proposed that induction of the diptericin gene mediated by the two 17 bp repeats occurs via a mechanism similar to that of mammalian NF-kappa B.}, keywords = {Animals, Anti-Bacterial Agents, Base Sequence, Cloning, Gene Expression Regulation, Genes, Genetic, Genetically Modified, hoffmann, Insect, Insect Hormones, Insect Proteins, Lipopolysaccharides, M3i, messenger, Molecular, NF-kappa B, Nucleic Acid, Oligodeoxyribonucleotides, Promoter Regions, Regulatory Sequences, reichhart, RNA, Transfection}, pubstate = {published}, tppubtype = {article} } The Drosophila diptericin gene codes for a 9 kDa antibacterial peptide and is rapidly and transiently expressed in larvae and adults after bacterial challenge. It is also induced in a tumorous Drosophila blood cell line by the addition of lipopolysaccharide (LPS). The promoter of this gene contains two 17 bp repeats located closely upstream of the TATA-box and harbouring a decameric kappa B-related sequence. This study reports that the replacement of the two 17 bp repeats by random sequences abolishes bacteria inducibility in transgenic fly lines. In transfected tumorous blood cells, the replacement of both or either of the 17 bp motifs reduces dramatically LPS inducibility, whereas multiple copies significantly increase the level of transcriptional activation by LPS challenge. A specific DNA-protein binding activity is evidenced in cytoplasmic and nuclear extracts of induced blood cells and fat body. It is absent in controls. It is proposed that induction of the diptericin gene mediated by the two 17 bp repeats occurs via a mechanism similar to that of mammalian NF-kappa B. |
Reichhart, Jean-Marc; Georgel, Philippe; Meister, Marie; Lemaitre, Bruno; Kappler, Christine; Hoffmann, Jules A Expression and nuclear translocation of the rel/NF-kappa B-related morphogen dorsal during the immune response of Drosophila Article de journal C. R. Acad. Sci. III, Sci. Vie, 316 (10), p. 1218–1224, 1993, ISSN: 0764-4469. Résumé | BibTeX | Étiquettes: Animals, Blotting, Cellular, Gene Expression, Genes, Genetic, hoffmann, Immunity, Insect, M3i, NF-kappa B, Northern, reichhart, translocation, Zygote @article{reichhart_expression_1993, title = {Expression and nuclear translocation of the rel/NF-kappa B-related morphogen dorsal during the immune response of Drosophila}, author = {Jean-Marc Reichhart and Philippe Georgel and Marie Meister and Bruno Lemaitre and Christine Kappler and Jules A Hoffmann}, issn = {0764-4469}, year = {1993}, date = {1993-01-01}, journal = {C. R. Acad. Sci. III, Sci. Vie}, volume = {316}, number = {10}, pages = {1218--1224}, abstract = {The rel/NF-kappa B-related morphogen dorsal is a maternally expressed gene which is involved in the control of the dorso-ventral axis during early embryogenesis of Drosophila. We show that this gene is also expressed in the fat body of larvae and adults of Drosophila as well as in a tumorous blood cell line: its expression is noticeably enhanced upon bacterial (or lipopolysaccharide) challenge. This challenge also induces within 15-30 min a nuclear translocation of the dorsal protein. The genes encoding inducible antibacterial peptides in Drosophila contain kappa B-related nucleotide sequences and we show that the dorsal protein can bind to such motifs and sequence-specifically transactivate a reporter gene in co-transfection experiments with a Drosophila cell line. However, in dl1 mutants, in the absence of dorsal protein, the genes encoding antibacterial peptides retain their inducibility, suggesting a multifactorial control. The results indicate that in addition to its role in embryogenesis, dorsal is involved in the immune response of Drosophila. They also strengthen the analogy between the mammalian acute phase response and the insect immune response.}, keywords = {Animals, Blotting, Cellular, Gene Expression, Genes, Genetic, hoffmann, Immunity, Insect, M3i, NF-kappa B, Northern, reichhart, translocation, Zygote}, pubstate = {published}, tppubtype = {article} } The rel/NF-kappa B-related morphogen dorsal is a maternally expressed gene which is involved in the control of the dorso-ventral axis during early embryogenesis of Drosophila. We show that this gene is also expressed in the fat body of larvae and adults of Drosophila as well as in a tumorous blood cell line: its expression is noticeably enhanced upon bacterial (or lipopolysaccharide) challenge. This challenge also induces within 15-30 min a nuclear translocation of the dorsal protein. The genes encoding inducible antibacterial peptides in Drosophila contain kappa B-related nucleotide sequences and we show that the dorsal protein can bind to such motifs and sequence-specifically transactivate a reporter gene in co-transfection experiments with a Drosophila cell line. However, in dl1 mutants, in the absence of dorsal protein, the genes encoding antibacterial peptides retain their inducibility, suggesting a multifactorial control. The results indicate that in addition to its role in embryogenesis, dorsal is involved in the immune response of Drosophila. They also strengthen the analogy between the mammalian acute phase response and the insect immune response. |