M3i

@article{fukuyama_landscape_2013,

title = {Landscape of protein-protein interactions in Drosophila immune deficiency signaling during bacterial challenge},

author = {Hidehiro Fukuyama and Yann Verdier and Yongsheng Guan and Chieko Makino-Okamura and Victoria Shilova and Xi Liu and Elie Maksoud and Jun Matsubayashi and Iman Haddad and Kerstin Spirohn and Kenichiro Ono and Charles Hetru and Jean Rossier and Trey Ideker and Michael Boutros and Joëlle Vinh and Jules A Hoffmann},

doi = {10.1073/pnas.1304380110},

issn = {1091-6490},

year  = {2013},

date = {2013-06-01},

journal = {Proc. Natl. Acad. Sci. U.S.A.},

volume = {110},

number = {26},

pages = {10717--10722},

abstract = {The Drosophila defense against pathogens largely relies on the activation of two signaling pathways: immune deficiency (IMD) and Toll. The IMD pathway is triggered mainly by Gram-negative bacteria, whereas the Toll pathway responds predominantly to Gram-positive bacteria and fungi. The activation of these pathways leads to the rapid induction of numerous NF-κB-induced immune response genes, including antimicrobial peptide genes. The IMD pathway shows significant similarities with the TNF receptor pathway. Recent evidence indicates that the IMD pathway is also activated in response to various noninfectious stimuli (i.e., inflammatory-like reactions). To gain a better understanding of the molecular machinery underlying the pleiotropic functions of this pathway, we first performed a comprehensive proteomics analysis to identify the proteins interacting with the 11 canonical members of the pathway initially identified by genetic studies. We identified 369 interacting proteins (corresponding to 291 genes) in heat-killed Escherichia coli-stimulated Drosophila S2 cells, 92% of which have human orthologs. A comparative analysis of gene ontology from fly or human gene annotation databases points to four significant common categories: (i) the NuA4, nucleosome acetyltransferase of H4, histone acetyltransferase complex, (ii) the switching defective/sucrose nonfermenting-type chromatin remodeling complex, (iii) transcription coactivator activity, and (iv) translation factor activity. Here we demonstrate that sumoylation of the IκB kinase homolog immune response-deficient 5 plays an important role in the induction of antimicrobial peptide genes through a highly conserved sumoylation consensus site during bacterial challenge. Taken together, the proteomics data presented here provide a unique avenue for a comparative functional analysis of proteins involved in innate immune reactions in flies and mammals.},

keywords = {Amino Acid, Animals, Chromatin Assembly and Disassembly, Escherichia coli, functional proteomics, Genes, Genetically Modified, Histone Acetyltransferases, hoffmann, Host-Pathogen Interactions, Humans, IMD interactome, Insect, M3i, Models, Molecular, Protein Interaction Maps, Sequence Homology, Signal Transduction, small ubiquitin-like modifier},

pubstate = {published},

tppubtype = {article}

}

@article{liu_drosophila_2012,

title = {Drosophila EYA regulates the immune response against DNA through an evolutionarily conserved threonine phosphatase motif},

author = {Xi Liu and Teruyuki Sano and Yongsheng Guan and Shigekazu Nagata and Jules A Hoffmann and Hidehiro Fukuyama},

doi = {10.1371/journal.pone.0042725},

issn = {1932-6203},

year  = {2012},

date = {2012-01-01},

journal = {PLoS ONE},

volume = {7},

number = {8},

pages = {e42725},

abstract = {Innate immune responses against DNA are essential to counter both pathogen infections and tissue damages. Mammalian EYAs were recently shown to play a role in regulating the innate immune responses against DNA. Here, we demonstrate that the unique Drosophila eya gene is also involved in the response specific to DNA. Haploinsufficiency of eya in mutants deficient for lysosomal DNase activity (DNaseII) reduces antimicrobial peptide gene expression, a hallmark for immune responses in flies. Like the mammalian orthologues, Drosophila EYA features a N-terminal threonine and C-terminal tyrosine phosphatase domain. Through the generation of a series of mutant EYA fly strains, we show that the threonine phosphatase domain, but not the tyrosine phosphatase domain, is responsible for the innate immune response against DNA. A similar role for the threonine phosphatase domain in mammalian EYA4 had been surmised on the basis of in vitro studies. Furthermore EYA associates with IKKβ and full-length RELISH, and the induction of the IMD pathway-dependent antimicrobial peptide gene is independent of SO. Our data provide the first in vivo demonstration for the immune function of EYA and point to their conserved immune function in response to endogenous DNA, throughout evolution.},

keywords = {Amino Acid, Animals, Blotting, Conserved Sequence, Endodeoxyribonucleases, Eye Proteins, hoffmann, Immunoprecipitation, M3i, Phosphoprotein Phosphatases, Sequence Homology, Transcription Factors, Western},

pubstate = {published},

tppubtype = {article}

}

@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 = {Amino Acid, Animals, Apoptosis, Biomphalaria, Blotting, Cell Proliferation, Cells, Cricetinae, Cultured, Hemocytes, Host-Parasite Interactions, Humans, Liver, M3i, Macrophage Migration-Inhibitory Factors, messenger, Oocysts, Recombinant Proteins, reichhart, Reverse Transcriptase Polymerase Chain Reaction, RNA, Schistosoma mansoni, Schistosomiasis mansoni, Sequence Homology, Small Interfering, Western},

pubstate = {published},

tppubtype = {article}

}

@article{,

title = {The role of mRNA structure in translational control in bacteria},

author = {T Geissmann and S Marzi and P Romby},

url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19885993},

isbn = {19885993},

year  = {2009},

date = {2009-01-01},

journal = {RNA Biol},

volume = {6},

number = {2},

pages = {153-160},

abstract = {During the past few years, our knowledge on RNA-based regulation in many organisms has tremendously increased. In bacteria, although transcriptional regulatory proteins remain key players in gene regulation, a wide variety of post-transcriptional regulatory mechanisms discovered highlights the importance of the mRNA structure in the regulation of gene expression. RNA-dependent regulation largely contributes to rapidly adapt the bacterial metabolism in response to environmental changes, stress and in establishment of virulence. Bacteria exploit the extraordinary ability of mRNA to fold into different structures in response to various signals (environmental cues, ligand binding). Induced mRNA conformational rearrangements can potentially regulate transcription, translation and mRNA stability. The present review focuses on the structures of regulatory regions of mRNA that have evolved to permit productive interactions with trans-acting regulators, such as protein or non-coding RNAs. Finally, we describe how particular properties of these regulatory complexes regulate translation initiation.},

note = {1555-8584 (Electronic) 

1547-6286 (Linking) 

Journal Article 

Research Support, Non-U.S. Gov't 

Review},

keywords = {Amino Acid, Amino Acid Sequence Bacteria/*genetics Bacterial Proteins/chemistry/genetics Molecular Sequence Data *Nucleic Acid Conformation *Protein Biosynthesis RNA, Messenger/*chemistry  Sequence Homology, ROMBY, Unité ARN},

pubstate = {published},

tppubtype = {article}

}

@article{,

title = {Plasmodial aspartyl-tRNA synthetases and peculiarities in Plasmodium falciparum},

author = {T Bour and A Akaddar and B Lorber and S Blais and C Balg and E Candolfi and M Frugier},

url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19443655},

isbn = {19443655},

year  = {2009},

date = {2009-01-01},

journal = {J Biol Chem},

volume = {284},

number = {28},

pages = {18893-18903},

abstract = {Distinctive features of aspartyl-transfer RNA (tRNA) synthetases (AspRS) from the protozoan Plasmodium genus are described. These apicomplexan AspRSs contain 29-31 amino acid insertions in their anticodon binding domains, a remarkably long N-terminal appendix that varies in size from 110 to 165 amino acids and two potential initiation codons. This article focuses on the atypical functional and structural properties of Plasmodium falciparum cytosolic AspRS, the causative parasite of human malaria. This species encodes a 626 or 577 amino acids AspRS depending on whether initiation starts on the first or second in-frame initiation codon. The longer protein has poor solubility and a propensity to aggregate. Production of the short version was favored as shown by the comparison of the recombinant protein with endogenous AspRS. Comparison of the tRNA aminoacylation activity of wild-type and mutant parasite AspRSs with those of yeast and human AspRSs revealed unique properties. The N-terminal extension contains a motif that provides unexpectedly strong RNA binding to plasmodial AspRS. Furthermore, experiments demonstrated the requirement of the plasmodial insertion for AspRS dimerization and, therefore, tRNA aminoacylation and other putative functions. Implications for the parasite biology are proposed. These data provide a robust background for unraveling the precise functional properties of the parasite AspRS and for developing novel lead compounds against malaria, targeting its idiosyncratic domains.},

note = {0021-9258 (Print) 

0021-9258 (Linking) 

Journal Article 

Research Support, Non-U.S. Gov't},

keywords = {Amino Acid, Amino Acid Sequence Amino Acids/chemistry Animals Aspartate-tRNA Ligase/*metabolism Aspartic Acid/chemistry Base Sequence Cloning, FRUGIER, Molecular  Cytoplasm/metabolism  Dimerization  Fungal Proteins/chemistry  Humans  Kinetics  Molecular Sequence Data  Plasmodium falciparum  Protein Structure, Tertiary  Sequence Homology, Unité ARN},

pubstate = {published},

tppubtype = {article}

}

@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 = {Amino Acid, Animals, Electrophoresis, Fat Body, Gene Expression Regulation, Genetic, Genetically Modified, hoffmann, Humans, imler, M3i, matt, Phylogeny, Polyacrylamide Gel, Reverse Transcriptase Polymerase Chain Reaction, Ribonuclease III, RNA Helicases, Sequence Homology, Transcription, Virus Diseases},

pubstate = {published},

tppubtype = {article}

}

@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 Alan R 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 = {Amino Acid, Amino Acid Motifs, Animals, Bacterial Infections, Cell Surface, Embryo, Escherichia coli, ferrandon, Flow Cytometry, Frameshift Mutation, Genes, Histidine, hoffmann, In Situ Hybridization, Insect, Insect Proteins, M3i, Macrophages, Membrane Proteins, messenger, Nonmammalian, Open Reading Frames, Phagocytosis, Receptors, reichhart, RNA, RNA Interference, Sequence Homology, Serratia marcescens},

pubstate = {published},

tppubtype = {article}

}

@article{weber_ligand-receptor_2005,

title = {Ligand-receptor and receptor-receptor interactions act in concert to activate signaling in the Drosophila toll pathway},

author = {Alexander N R Weber and Martin C Moncrieffe and Monique Gangloff and Jean-Luc Imler and Nicholas J Gay},

doi = {10.1074/jbc.M502074200},

issn = {0021-9258},

year  = {2005},

date = {2005-01-01},

journal = {The Journal of Biological Chemistry},

volume = {280},

number = {24},

pages = {22793--22799},

abstract = {In Drosophila, the signaling pathway mediated by the Toll receptor is critical for the establishment of embryonic dorso-ventral pattern and for innate immune responses to bacterial and fungal pathogens. Toll is activated by high affinity binding of the cytokine Spätzle, a dimeric ligand of the cystine knot family. In vertebrates, a related family of Toll-like receptors play a critical role in innate immune responses. Despite the importance of this family of receptors, little is known about the biochemical events that lead to receptor activation and signaling. Here, we show that Spätzle binds to the N-terminal region of Toll and, using biophysical methods, that the binding is complex. The two binding events that cause formation of the cross-linked complex are non-equivalent: the first Toll ectodomain binds Spätzle with an affinity 3-fold higher than the second molecule suggesting that pathway activation involves negative cooperativity. We further show that the Toll ectodomains are able to form low affinity dimers in solution and that juxtamembrane sequences of Toll are critical for the activation or derepression of the pathway. These results, taken together, suggest a mechanism of signal transduction that requires both ligand-receptor and receptor-receptor interactions.},

keywords = {Amino Acid, Animals, Biophysical Phenomena, Biophysics, Body Patterning, Calorimetry, Cell Line, Cell Surface, Cross-Linking Reagents, Cytokines, dimerization, Electrophoresis, Humans, imler, ligands, Luciferases, M3i, Membrane Glycoproteins, Polyacrylamide Gel, Protein Binding, Protein Structure, Receptors, Recombinant Proteins, Sequence Homology, Signal Transduction, Tertiary, Time Factors, Toll-Like Receptors, Ultracentrifugation},

pubstate = {published},

tppubtype = {article}

}

@article{tauszig-delamasure_drosophila_2002,

title = {Drosophila MyD88 is required for the response to fungal and Gram-positive bacterial infections},

author = {Servane Tauszig-Delamasure and Hana Bilak and Maria Capovilla and Jules A Hoffmann and Jean-Luc Imler},

doi = {10.1038/ni747},

issn = {1529-2908},

year  = {2002},

date = {2002-01-01},

journal = {Nature Immunology},

volume = {3},

number = {1},

pages = {91--97},

abstract = {We report here the identification and functional characterization of DmMyD88, a gene encoding the Drosophila homolog of mammalian MyD88. DmMyD88 combines a Toll-IL-1R homology (TIR) domain and a death domain. Overexpression of DmMyD88 was sufficient to induce expression of the antifungal peptide Drosomycin, and induction of Drosomycin was markedly reduced in DmMyD88-mutant flies. DmMyD88 interacted with Toll through its TIR domain and required the death domain proteins Tube and Pelle to activate expression of Drs, which encodes Drosomycin. DmMyD88-mutant flies were highly susceptible to infection by fungi and Gram-positive bacteria, but resisted Gram-negative bacterial infection much as did wild-type flies. Phenotypic comparison of DmMyD88-mutant flies and MyD88-deficient mice showed essential differences in the control of Gram-negative infection in insects and mammals.},

keywords = {Adaptor Proteins, Amino Acid, Animals, Antigens, Antimicrobial Cationic Peptides, Cell Surface, Chromosome Mapping, Differentiation, Disease Susceptibility, Enterococcus faecalis, Epistasis, Escherichia coli, Female, Gene Expression Regulation, Genes, Genetic, Genetically Modified, Gram-Negative Bacteria, hoffmann, Hypocreales, imler, Immunologic, Insect, Insect Proteins, M3i, Membrane Glycoproteins, Micrococcus luteus, Myeloid Differentiation Factor 88, Protein Structure, Protein-Serine-Threonine Kinases, Receptors, Recombinant Fusion Proteins, Sequence Alignment, Sequence Homology, Signal Transducing, Tertiary, Toll-Like Receptors, Transfection},

pubstate = {published},

tppubtype = {article}

}

@article{michel_drosophila_2001,

title = {Drosophila Toll is activated by Gram-positive bacteria through a circulating peptidoglycan recognition protein},

author = {T Michel and Jean-Marc Reichhart and Jules A Hoffmann and Julien Royet},

doi = {10.1038/414756a},

issn = {0028-0836},

year  = {2001},

date = {2001-12-01},

journal = {Nature},

volume = {414},

number = {6865},

pages = {756--759},

abstract = {Microbial infection activates two distinct intracellular signalling cascades in the immune-responsive fat body of Drosophila. Gram-positive bacteria and fungi predominantly induce the Toll signalling pathway, whereas Gram-negative bacteria activate the Imd pathway. Loss-of-function mutants in either pathway reduce the resistance to corresponding infections. Genetic screens have identified a range of genes involved in these intracellular signalling cascades, but how they are activated by microbial infection is largely unknown. Activation of the transmembrane receptor Toll requires a proteolytically cleaved form of an extracellular cytokine-like polypeptide, Spätzle, suggesting that Toll does not itself function as a bona fide recognition receptor of microbial patterns. This is in apparent contrast with the mammalian Toll-like receptors and raises the question of which host molecules actually recognize microbial patterns to activate Toll through Spätzle. Here we present a mutation that blocks Toll activation by Gram-positive bacteria and significantly decreases resistance to this type of infection. The mutation semmelweis (seml) inactivates the gene encoding a peptidoglycan recognition protein (PGRP-SA). Interestingly, seml does not affect Toll activation by fungal infection, indicating the existence of a distinct recognition system for fungi to activate the Toll pathway.},

keywords = {Amino Acid, Animals, Anti-Bacterial Agents, Anti-Infective Agents, Bacillus thuringiensis, Carrier Proteins, Cell Surface, Chromosome Mapping, Enterococcus faecalis, Fungi, Genes, Gram-Positive Bacteria, Hemolymph, hoffmann, Humans, Insect, Insect Proteins, M3i, Membrane Glycoproteins, Micrococcus luteus, Mutation, Receptors, reichhart, Sequence Homology, Toll-Like Receptors},

pubstate = {published},

tppubtype = {article}

}

@article{lamberty_insect_2001,

title = {Insect immunity. Constitutive expression of a cysteine-rich antifungal and a linear antibacterial peptide in a termite insect.},

author = {M Lamberty and Daniel Zachary and R Lanot and C Bordereau and A Robert and Jules A Hoffmann and Philippe Bulet},

doi = {10.1074/jbc.M002998200},

issn = {0021-9258},

year  = {2001},

date = {2001-02-01},

journal = {J. Biol. Chem.},

volume = {276},

number = {6},

pages = {4085--4092},

abstract = {Two novel antimicrobial peptides, which we propose to name termicin and spinigerin, have been isolated from the fungus-growing termite Pseudacanthotermes spiniger (heterometabole insect, Isoptera). Termicin is a 36-amino acid residue antifungal peptide, with six cysteines arranged in a disulfide array similar to that of insect defensins. In contrast to most insect defensins, termicin is C-terminally amidated. Spinigerin consists of 25 amino acids and is devoid of cysteines. It is active against bacteria and fungi. Termicin and spinigerin show no obvious sequence similarities with other peptides. Termicin is constitutively present in hemocyte granules and in salivary glands. The presence of termicin and spinigerin in unchallenged termites contrasts with observations in evolutionary recent insects or insects undergoing complete metamorphosis, in which antimicrobial peptides are induced in the fat body and released into the hemolymph after septic injury.},

keywords = {Amino Acid, Animals, Anti-Bacterial Agents, Antifungal Agents, Base Sequence, Chromatography, Cysteine, DNA Primers, High Pressure Liquid, hoffmann, Immunohistochemistry, Isoptera, M3i, Peptides, Protein Conformation, Recombinant Proteins, Sequence Homology},

pubstate = {published},

tppubtype = {article}

}

@article{lagueux_constitutive_2000,

title = {Constitutive expression of a complement-like protein in toll and JAK gain-of-function mutants of Drosophila},

author = {Marie Lagueux and E Perrodou and Elena A Levashina and Maria Capovilla and Jules A Hoffmann},

doi = {10.1073/pnas.97.21.11427},

issn = {0027-8424},

year  = {2000},

date = {2000-10-01},

journal = {Proc. Natl. Acad. Sci. U.S.A.},

volume = {97},

number = {21},

pages = {11427--11432},

abstract = {We show that Drosophila expresses four genes encoding proteins with significant similarities with the thiolester-containing proteins of the complement C3/alpha(2)-macroglobulin superfamily. The genes are transcribed at a low level during all stages of development, and their expression is markedly up-regulated after an immune challenge. For one of these genes, which is predominantly expressed in the larval fat body, we observe a constitutive expression in gain-of-function mutants of the Janus kinase (JAK) hop and a reduced inducibility in loss-of-function hop mutants. We also observe a constitutive expression in gain-of-function Toll mutants. We discuss the possible roles of these novel complement-like proteins in the Drosophila host defense.},

keywords = {alpha-Macroglobulins, Amino Acid, Animals, Cell Surface, Complement C3, Esters, Genetic, hoffmann, Insect Proteins, Janus Kinases, M3i, Membrane Glycoproteins, Mutation, Protein-Tyrosine Kinases, Proteins, Receptors, Sequence Homology, Sulfhydryl Compounds, Toll-Like Receptors, Transcription, Transcription Factors},

pubstate = {published},

tppubtype = {article}

}

@article{tauszig_toll-related_2000,

title = {Toll-related receptors and the control of antimicrobial peptide expression in Drosophila},

author = {Servane Tauszig and Emmanuelle Jouanguy and Jules A Hoffmann and Jean-Luc Imler},

doi = {10.1073/pnas.180130797},

issn = {0027-8424},

year  = {2000},

date = {2000-09-01},

journal = {Proceedings of the National Academy of Sciences of the United States of America},

volume = {97},

number = {19},

pages = {10520--10525},

abstract = {Insects defend themselves against infectious microorganisms by synthesizing potent antimicrobial peptides. Drosophila has appeared in recent years as a favorable model to study this innate host defense. A genetic analysis of the regulation of the antifungal peptide drosomycin has demonstrated a key role for the transmembrane receptor Toll, which prompted the search for mammalian homologs. Two of these, Toll-like receptor (TLR)2 and TLR4, recently were shown to play a critical role in innate immunity against bacteria. Here we describe six additional Toll-related genes (Toll-3 to Toll-8) in Drosophila in addition to 18-wheeler. Two of these genes, Toll-3 and Toll-4, are expressed at a low level. Toll-6, -7, and -8, on the other hand, are expressed at high levels during embryogenesis and molting, suggesting that, like Toll and 18w, they perform developmental functions. Finally, Toll-5 is expressed only in larvae and adults. By using chimeric constructs, we have tested the capacity of the signaling Toll/IL-1R homology domains of these receptors to activate antimicrobial peptide promoters and found that only Toll and Toll-5 can activate the drosomycin promoter in transfected cells, thus demonstrating specificity at the level of the Toll/IL-1R homology domain. In contrast, none of these constructs activated antibacterial peptide promoters, suggesting that Toll-related receptors are not involved in the regulation of antibacterial peptide expression. This result was independently confirmed by the demonstration that a dominant-negative version of the kinase Pelle can block induction of drosomycin by the cytokine Spaetzle, but does not affect induction of the antibacterial peptide attacin by lipopolysaccharide.},

keywords = {Amino Acid, Animals, Anti-Bacterial Agents, Blotting, Cell Line, Cell Surface, hoffmann, imler, M3i, Membrane Glycoproteins, Multigene Family, Northern, Peptides, Receptors, Reverse Transcriptase Polymerase Chain Reaction, Sequence Homology, Toll-Like Receptor 2, Toll-Like Receptor 4, Toll-Like Receptor 5, Toll-Like Receptors},

pubstate = {published},

tppubtype = {article}

}

@article{lamberty_insect_1999,

title = {Insect immunity. Isolation from the lepidopteran Heliothis virescens of a novel insect defensin with potent antifungal activity},

author = {M Lamberty and S Ades and S Uttenweiler-Joseph and G Brookhart and D Bushey and Jules A Hoffmann and Philippe Bulet},

issn = {0021-9258},

year  = {1999},

date = {1999-04-01},

journal = {J. Biol. Chem.},

volume = {274},

number = {14},

pages = {9320--9326},

abstract = {Lepidoptera have been reported to produce several antibacterial peptides in response to septic injury. However, in marked contrast to other insect groups, no inducible antifungal molecules had been described so far in this insect order. Surprisingly, also cysteine-rich antimicrobial peptides, which predominate in the antimicrobial defense of other insects, had not been discovered in Lepidoptera. Here we report the isolation from the hemolymph of immune induced larvae of the lepidopteran Heliothis virescens of a cysteine-rich molecule with exclusive antifungal activity. We have fully characterized this antifungal molecule, which has significant homology with the insect defensins, a large family of antibacterial peptides directed against Gram-positive strains. Interestingly, the novel peptide shows also similarities with the antifungal peptide drosomycin from Drosophila. Thus, Lepidoptera appear to have built their humoral immune response against bacteria on cecropins and attacins. In addition, we report that Lepidoptera have conferred antifungal properties to the well conserved structure of antibacterial insect defensins through amino acid replacements.},

keywords = {Amino Acid, Animals, Antifungal Agents, Capillary, Chromatography, Defensins, Electrophoresis, Escherichia coli, Hemolymph, High Pressure Liquid, hoffmann, Insect Proteins, Larva, Lepidoptera, M3i, Micrococcus luteus, Proteins, Sequence Homology},

pubstate = {published},

tppubtype = {article}

}

@article{lowenberger_insect_1999,

title = {Insect immunity: molecular cloning, expression, and characterization of cDNAs and genomic DNA encoding three isoforms of insect defensin in Aedes aegypti},

author = {C A Lowenberger and C T Smartt and Philippe Bulet and M T Ferdig and D W Severson and Jules A Hoffmann and B M Christensen},

issn = {0962-1075},

year  = {1999},

date = {1999-02-01},

journal = {Insect Mol. Biol.},

volume = {8},

number = {1},

pages = {107--118},

abstract = {Aedes aegypti were immune activated by injection with bacteria, and the expression of insect defensins was measured over time. Northern analyses indicated that defensin transcriptional activity continued for at least 21 days after bacterial injection, and up to 10 days after saline inoculation. Mature defensin levels in the haemolymph reached approximately 45 microM at 24 h post inoculation. cDNAs encoding the preprodefensins of three previously described mature Ae. aegypti defensins were amplified by PCR, cloned and sequenced. Genomic clones were amplified using primers designed against the cDNA sequence. Sequence comparison indicates that there is significant inter- and intra-isoform variability in the signal peptide and prodefensin sequences of defensin genes. Preprodefensin sequences of isoforms A and B are very similar, consisting of a signal peptide region of twenty amino acids, a prodefensin region of thirty-eight amino acids and a forty amino acid mature peptide domain. The sequence encoding isoform C is significantly different, comprising a signal peptide region of twenty-three amino acids, a prodefensin region of thirty-six amino acids, and the mature protein domain of forty amino acids. Analysis of the genomic clones of each isoform revealed one intron spatially conserved in the prodefensin region of all sequences. The intron in isoforms A and B is 64 nt long, and except for a 4 nt substitution in one clone, these intron sequences are identical. The intron in isoform C is 76 nt long and does not share significant identity with the intron sequences of isoforms A or B. The defensin gene mapped to chromosome 3, between two known loci, blt and LF168.},

keywords = {Aedes, Amino Acid, Animals, Base Sequence, Blotting, Chromosome Mapping, Cloning, Complementary, Defensins, DNA, Gene Expression, Hemolymph, hoffmann, M3i, Molecular, Northern, Protein Isoforms, Proteins, Sequence Homology},

pubstate = {published},

tppubtype = {article}

}

@article{taguchi_novel_1998,

title = {A novel insect defensin from the ant Formica rufa},

author = {S Taguchi and Philippe Bulet and Jules A Hoffmann},

issn = {0300-9084},

year  = {1998},

date = {1998-04-01},

journal = {Biochimie},

volume = {80},

number = {4},

pages = {343--346},

abstract = {By combination of size exclusion and reversed-phase chromatography, we have isolated a novel member of insect defensin-type antimicrobial peptides from the entire bodies of bacteria-challenged Formica rufa (hymenoptera, formicidae). The molecular mass of the purified peptide was estimated to be 4120.42 by matrix-assisted laser desorption/ionization-time of flight/mass spectrometry. Sequence analysis revealed that this peptide consisted of 40 amino acid residues with six cysteines engaged in the formation of three intramolecular disulfide bridges. This peptide is unique among the arthropod defensins in terms of the presence of asparatic acid and alanine at position 33 and as C-terminal residue, respectively. In addition, this novel defensin from Formica rufa has the particularity to have no C-terminal extension in contrast to those reported for other hymenoptera defensins.},

keywords = {Amino Acid, Animals, Anti-Bacterial Agents, Ants, Chromatography, High Pressure Liquid, hoffmann, Insect Proteins, insects, M3i, Mass, Matrix-Assisted Laser Desorption-Ionization, Protein Structure, Secondary, Sequence Alignment, Sequence Homology, Spectrometry},

pubstate = {published},

tppubtype = {article}

}

@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}

}

@article{charlet_innate_1996,

title = {Innate immunity. Isolation of several cysteine-rich antimicrobial peptides from the blood of a mollusc, Mytilus edulis},

author = {Maurice Charlet and S Chernysh and H Philippe and Charles Hetru and Jules A Hoffmann and Philippe Bulet},

issn = {0021-9258},

year  = {1996},

date = {1996-09-01},

journal = {J. Biol. Chem.},

volume = {271},

number = {36},

pages = {21808--21813},

abstract = {We have isolated from the blood of immune-challenged and untreated mussels (Mytilus edulis) antibacterial and antifungal peptides. We have characterized two isoforms of a novel 34-residue, cysteine-rich, peptide with potent bactericidal activity and partially characterized a novel 6.2-kDa antifungal peptide containing 12 cysteines. We report the presence of two members of the insect defensin family of antibacterial peptides and provide a phylogenetic analysis that indicates that mollusc and arthropod defensins have a common ancestry. Our data argue that circulating antimicrobial peptides represent an ancient host defense mechanism that predated the separation between molluscs and arthropods at the root of the Cambrian, about 545 million years ago.},

keywords = {Amino Acid, Animals, Anti-Infective Agents, Antifungal Agents, Bivalvia, Blood Proteins, Chromatography, Cysteine, Defensins, High Pressure Liquid, hoffmann, M3i, Molecular Weight, Phylogeny, Sequence Homology},

pubstate = {published},

tppubtype = {article}

}