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Toll Receptors in Drosophila: a Family of Molecules Regulating Development and Immunity

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Toll-Like Receptor Family Members and Their Ligands

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 270))

Abstract

In recent years, Toll-like receptors (TLRs) have emerged as key receptors which detect microbes and initiate an inflammatory response. The Toll receptor was originally identified and characterized 14 years ago for its role in the embryonic development of the fruit-flyDrosophila melanogaster. Subsequently, it was also shown to be an essential component of the signaling pathway mediating the anti-fungal host defense in this model organism. New factors involved in the activation of the Toll receptor or in intracytoplasmic signaling during the immune response inDrosophila have recently been identified. The existence of significant functional differences between mammalian TLRs andDrosophila Toll receptors is also becoming apparent.

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References

  • Anderson KV (2000) Toll signaling pathways in the innate immune response. Curr Opin Immunol 12: 13–19

    Article  PubMed  CAS  Google Scholar 

  • Anderson KV, Nusslein-Volhard C (1984) Information for the dorsal-ventral pattern of the Drosophila embryo is stored as maternal mRNA. Nature 311: 223–227

    Article  PubMed  CAS  Google Scholar 

  • Belvin MP, Anderson KV (1996) A conserved signaling pathway: the Drosophila toll-dorsal pathway. Ann Rev Cell Dev Biol 12: 393–416

    Article  CAS  Google Scholar 

  • Bergner A, Oganessyan V, Muta T, Iwanaga S, Typke D, Huber R, Bode W (1996) Crystal structure of a coagulogen, the clotting protein from horseshoe crab: a structural homologue of nerve growth factor. EMBO J 15: 6789–6797

    PubMed  Google Scholar 

  • Cao Z, Xiong J, Takeuchi M, Kurama T, Goeddel DV (1996) TRAF6 is a signal transducer for interleukin-1. Nature 383: 443–446

    Article  PubMed  CAS  Google Scholar 

  • Clemens JC, Worby CA, Simonson-Leff N, Muda M, Maehama T, Hemmings BA, Dixon JE (2000) Use of double-stranded RNA interference in Drosophila cell lines to dissect signal transduction pathways. Proc Natl Acad Sci USA 97: 6499–6503

    Article  PubMed  CAS  Google Scholar 

  • DeLotto Y, DeLotto R (1998) Proteolytic processing of the Drosophila Spatzle protein by easter generates a dimeric NGF-like molecule with ventralising activity. Mech Dev 72: 141–148

    Article  PubMed  CAS  Google Scholar 

  • Dissing M, Giordano H, DeLotto R (2001) Autoproteolysis and feedback in a protease cascade directing Drosophila dorsal-ventral cell fate. EMBO J 20: 2387–2393

    Article  PubMed  CAS  Google Scholar 

  • Drier EA, Govind S, Steward R (2000) Cactus-independent regulation of Dorsal nuclear import by the ventral signal. Curr Biol 10: 23–26

    Article  PubMed  CAS  Google Scholar 

  • Du X, Poltorak A, Wei Y, Beutler B (2000) Three novel mammalian toll-like receptors: gene structure, expression, and evolution. Eur Cytokine Netw 11: 362–371

    PubMed  CAS  Google Scholar 

  • Edwards DN, Towb P, Wasserman SA (1997) An activity-dependent network of interactions links the Rel protein Dorsal with its cytoplasmic regulators. Development 124: 3855–3864

    PubMed  CAS  Google Scholar 

  • Eldon E, Kooyer S, D’Evelyn D, Duman M, Lawinger P, Botas J, Bellen H (1994) The Drosophila 18 wheeler is required for morphogenesis and has striking similarities to Toll. Development 120: 885–899

    PubMed  CAS  Google Scholar 

  • Elrod-Erickson M, Mishra S, Schneider D (2000) Interactions between the cellular and humoral immune responses in Drosophila. Curr Biol 10: 781–784

    Article  PubMed  CAS  Google Scholar 

  • Engstrom Y, Kadayalil L, Sun S, Samakovlis C, Hultmark D, Faye I (1993) kB-like motifs regulate the induction of immune genes in Drosophila. J Mol Biol 232:327–333

    Article  PubMed  CAS  Google Scholar 

  • Galindo RL, Edwards DN, Gillespie SK, Wasserman SA (1995) Interaction of the pelle kinase with the membrane-associated protein tube is required for transduction of the dorsoventral signal in Drosophila embryos. Development 121: 2209–2218

    PubMed  CAS  Google Scholar 

  • Gay N, Keith F (1991) Drosophila Toll and IL-1 receptor. Nature 351: 355–356

    Article  PubMed  CAS  Google Scholar 

  • Georgel P, Naitza S, Kappler C, Ferrandon D, Zachary D, Swimmer C, Kopczynski C, Duyk G, Reichhart JM, Hoffmann JA (2001) Drosophila immune deficiency (IMD) is a death domain protein that activates the antibacterial response and can promote apoptosis. Development Cell 1 (4): 503–514

    Article  CAS  Google Scholar 

  • Grosshans J, Bergmann A, Haffter P, Nusslein-Volhard C (1994) Activation of the kinase Pelle by Tube in the dorsoventral signal transduction pathway of Drosophila embryo. Nature 372: 563–566

    Article  PubMed  CAS  Google Scholar 

  • Grosshans J, Schnorrer F, Nusslein-Volhard C (1999) Oligomerisation of Tube and Pelle leads to nuclear localisation of dorsal. Mech Dev 81: 127–138

    Article  PubMed  CAS  Google Scholar 

  • Halfon MS, Keshishian H (1998) The Toll pathway is required in the epidermis for muscle development in the Drosophila embryo. Dev Biol 199: 164–174

    Article  PubMed  CAS  Google Scholar 

  • Han JH, Lee SH, Tan YQ, LeMosy EK, Hashimoto C (2000) Gastrulation defective is a serine protease involved in activating the receptor toll to polarize the Drosophila embryo. Proc Natl Acad Sci USA 97: 9093–9097

    Article  PubMed  CAS  Google Scholar 

  • Hashimoto C, Hudson K, Anderson K (1988) The Toll gene of Drosophila, required for dorsal-ventral embryonic polarity, appears to encode a transmembrane protein. Cell 52: 269–279

    Article  PubMed  CAS  Google Scholar 

  • Hedengren M, Asling B, Dushay M, Ando I, Ekengren S, Wihlborg M, Hultmark D (1999) Relish, a Central Factor in the Control of Humoral but Not Cellular Immunity in Drosophila. Molecular Cell 4: 1–20

    Article  Google Scholar 

  • Hoffmann J, Reichhart J (1997) Drosophila immunity. Trends in Cell Biol 7: 309–316

    Article  CAS  Google Scholar 

  • Hong CC, Hashimoto C (1995) An unusual mosaic protein with a protease domain, encoded by the nudel gene, is involved in defining embryonic dorsoventral polarity in Drosophila. Cell 82: 785–794

    Article  PubMed  CAS  Google Scholar 

  • Horng T, Medzhitov R (2001) Drosophila MyD88 is an adapter in the Toll signaling pathway. Proc Natl Acad Sci USA 98: 12654–12658

    Article  PubMed  CAS  Google Scholar 

  • Imler JL, Tauszig S, Jouanguy E, Forestier C, Hoffmann JA (2000) LPS-induced immune response in Drosophila. J Endotoxin Res 6: 459–462

    PubMed  CAS  Google Scholar 

  • Ip Y, Reach M, Enstrom Y, Kadalayil L, Cai H, Gonzalez-Crespo S, Tatei K, Levine M (1993) Dif, adorsal-related gene that mediates an immune response in Drosophila. Cell 75: 753–763

    Article  PubMed  CAS  Google Scholar 

  • Keith J, Gay N (1990) The Drosophila membrane receptor Toll can function to promote cellular adhe¬sion. EMBO J 9: 4299–1306

    PubMed  CAS  Google Scholar 

  • Kim YS, Han SJ, Ryu JH, Choi KH, Hong YS, Chung YH, Perrot S, Raibaud A, Brey PT, Lee WJ (2000) Lipopolysaccharide-activated kinase, an essential component for the induction of the antimicrobial peptide genes in Drosophila melanogaster cells. J Biol Chem 275: 2071–2079

    Article  PubMed  CAS  Google Scholar 

  • Kopp E, Medzhitov R, Carothers J, Xiao C, Douglas I, Janeway CA, Ghosh S (1999) ECSIT is an evolutionarily conserved intermediate in the Toll/IL-1 signal transduction pathway. Genes Dev 13: 2059–2071

    Article  PubMed  CAS  Google Scholar 

  • Lemaitre B, Kromer-Metzger E, Michaut L, Nicolas E, Meister M, Georgel P, Reichhart J, Hoffmann J (1995a) A recessive mutation, immune deficiency (imd), defines two distinct control pathways in the Drosophila host defense. Proc Natl Acad Sci USA 92: 9365–9469

    Article  Google Scholar 

  • Lemaitre B, Meister M, Govind S, Georgel P, Steward R, Reichhart JM, Hoffmann JA (1995b) Functional analysis and regulation of nuclear import of dorsal during the immune response in Drosophila. EMBO J 14: 536–545

    CAS  Google Scholar 

  • Lemaitre B, Nicolas E, Michaut L, Reichhart J, Hoffmann J (1996) The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86: 973–983

    Article  PubMed  CAS  Google Scholar 

  • LeMosy EK, Hong CC, Hashimoto C (1999) Signal transduction by a protease cascade. Trends Cell Biol 9: 102–107

    Article  PubMed  CAS  Google Scholar 

  • LeMosy EK, Tan YQ, Hashimoto C (2001) Activation of a protease cascade involved in patterning the Drosophila embryo. Proc Natl Acad Sci USA 98: 5055–5060

    Article  PubMed  CAS  Google Scholar 

  • Letsou A, Alexander S, Orth K, Wasserman SA (1991) Genetic and molecular characterization of tube, a Drosophila gene maternally required for embryonic dorsoventral polarity. Proc Natl Acad Sci USA 88: 810–814

    Article  PubMed  CAS  Google Scholar 

  • Leulier F, Rodriguez A, Khush RS, Abrams JM, Lemaitre B (2000) The Drosophila caspase Dredd is required to resist Gram-negative bacterial infection. EMBO reports 1: 353–358

    Article  PubMed  CAS  Google Scholar 

  • Levashina EA, Langley E, Green C, Gubb D, Ashburner M, Hoffmann JA, Reichhart JM (1999) Constitutive activation of toll-mediated antifungal defense in serpin- deficient Drosophila. Science 285: 1917–1919

    Article  PubMed  CAS  Google Scholar 

  • Liu H, Su YC, Becker E, Treisman J, Skolnik EY (1999) A Drosophila TNF-receptor-associated factor (TRAF) binds the ste20 kinase Misshapen and activates Jun kinase. Curr Biol 9: 101–104

    Article  PubMed  CAS  Google Scholar 

  • Lu Y, Wu LP, Anderson KV (2001) The antibacterial arm of the Drosophila innate immune response requires an IKB kinase. Genes Dev 15: 104–110

    Article  PubMed  CAS  Google Scholar 

  • Luo C, Zheng L (2000) Independent evolution of Toll and related genes in insects and mammals. Immunogenetics 51: 92–98

    Article  PubMed  CAS  Google Scholar 

  • Manfruelli P, Reichhart JM, Steward R, Hoffmann JA, and Lemaitre B (1999) A mosaic analysis in Drosophila fat body cells of the control of antimicrobial peptide genes by the Rel proteins and DIF. EMBO J 18: 3380–3391

    Article  PubMed  CAS  Google Scholar 

  • McDonald N, Hendrickson W (1993) A structural superfamily of growth factors containing a cysteine knot motif. Cell 73: 421–424

    Article  PubMed  CAS  Google Scholar 

  • Meister M, Braun A, Kappler C, Reichhart JM, Hoffmann JA (1994) Insect immunity. A transgenic analysis in Drosophila defines several functional domains in the diptericin promoter. EMBO J 13: 5958–5966

    PubMed  CAS  Google Scholar 

  • Meng X, Khanuja BS, Ip YT (1999) Toll receptor-mediated Drosophila immune response requires Dif, an NF- kappaB factor. Genes Dev 13: 792–797

    Article  PubMed  CAS  Google Scholar 

  • Michel T, Reichhart JM, Hoffmann JA, Royet J (2001) Drosophila Toll is activated by Gram-positive bacteria through a circulating peptidoglycan recognition protein. Nature 414: 756–759

    Article  PubMed  CAS  Google Scholar 

  • Morisato D, Anderson K (1994) The spatzle gene encodes a component of the extracellular signaling pathway establishing the dorsal-ventral pattern of the Drosophila embryo. Cell 76: 677–688

    Article  PubMed  CAS  Google Scholar 

  • Muta T, Iwanaga S (1996) The role of hemolymph coagulation in innate immunity. Curr Opin Immunol 8: 41–47

    Article  PubMed  CAS  Google Scholar 

  • Nicolas E, Reichhart J, Hoffmann J, Lemaitre B (1998) In vivo regulation of the IKB homologue cactus during the immune response of Drosophila. J Biol Chem 273: 10463–10469

    Article  PubMed  CAS  Google Scholar 

  • Onfelt Tingvall T, Roos E, Engstrom Y (2001) The imd gene is required for local Cecropin expression in Drosophila barrier epithelia. EMBO Rep 2: 239–243

    Article  PubMed  CAS  Google Scholar 

  • Parker JS, Mizuguchi K, Gay NJ (2001) A family of proteins related to Spatzle, the toll receptor ligand, are encoded in the Drosophila genome. Proteins 45: 71–80

    Article  PubMed  CAS  Google Scholar 

  • Petersen UM, Kadalayil L, Rehorn KP, Hoshizaki DK, Reuter R, Engstrom Y (1999) Serpent regulates Drosophila immunity genes in the larval fat body through an essential GATA motif. EMBO J 18: 4013–4022

    Article  PubMed  CAS  Google Scholar 

  • Poltorak A, He X, Smirnova I, Liu M, Huffel C, Du X, Birdwell D, Alejos E, Silva M, Galanos C, Freudenberg M, Ricciardi-Castagnoli P, Layton B, Beutler B (1998) Defective LPS signaling in C3H/ HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282: 2085–2088

    Article  PubMed  CAS  Google Scholar 

  • Pujol N, Link EM, Liu LX, Kurz CL, Alloing G, Tan M, Ray KP, Solari R, Johnson CD, Ewbank JJ (2001) A reverse genetic analysis of components of the Toll signaling pathway in Caenorhabditis elegans. Curr Biol 11: 809–821

    Article  PubMed  CAS  Google Scholar 

  • Qiu P, Pan PC, Govind S (1998) A role for the Drosophila Toll/Cactus pathway in larval hematopoiesis. Development 125: 1909–1920

    PubMed  CAS  Google Scholar 

  • Rose D, Zhu X, Kose H, Hoang B, Cho J, Chiba A (1997) Toll, a muscle cell surface molecule, locally inhibits synaptic initiation of the RP3 motoneuron growth cone in Drosophila. Development 124: 1561–1571

    PubMed  CAS  Google Scholar 

  • Rutschmann S, Jung A, Hetru C, Reichhart J, Hoffmann J, Ferrandon D (2000a) The Rel protein DIF. mediates the Toll-dependent antifungal response in Drosophila. Immunity 12: 569–580

    Article  CAS  Google Scholar 

  • Rutschmann S, Jung A, Zhou R, Silverman N, Hoffmann JA, Ferrandon D (2000b) Role of Drosophila IKKy in a Toll-independent antibacterial immune response. Nature Immunol 1: 342–347

    Article  CAS  Google Scholar 

  • Rutschmann S, Kilinc A, Ferrandon D (2002) The Toll pathway is required for resistance to Gram-positive bacterial infections in Drosophila. J Immunol 168: 1542–1546

    PubMed  CAS  Google Scholar 

  • Schiffmann DA, White JH, Cooper A, Nutley MA, Harding SE, Jumel K, Solari R, Ray KP, Gay NJ (1999) Formation and biochemical characterization of tube/pelle death domain complexes: critical regulators of postreceptor signaling by the Drosophila toll receptor. Biochemistry 38: 11722–11733

    Article  PubMed  CAS  Google Scholar 

  • Schneider D, Hudson K, Lin T, Anderson K (1991) Dominant and recessive mutations define functional domains of Toll, a transmembrane protein required for dorsal-ventral polarity in the Drosophila embryo. Genes & Dev 5: 797–807

    Article  CAS  Google Scholar 

  • Sen J, Goltz JS, Konsolaki M, Schupbach T, Stein D (2000) Windbeutel is required for function and correct subcellular localization of the Drosophila patterning protein Pipe. Development 127: 5541–5550

    PubMed  CAS  Google Scholar 

  • Shelton CA, Wasserman SA (1993) pelle encodes a protein kinase required to establish dorsoventral polarity in the Drosophila embryo. Cell 72:515–525

    Article  PubMed  CAS  Google Scholar 

  • Shen B, Liu H, Skolnik EY, Manley JL (2001) Physical and functional interactions between Drosophila TRAF2 and Pelle kinase contribute to Dorsal activation. Proc Natl Acad Sci USA 98: 8596–8601

    Article  PubMed  CAS  Google Scholar 

  • Shen B, Manley JL (1998) Phosphorylation modulates direct interactions between the Toll receptor, Pelle kinase and Tube. Development 125: 4719–4728

    PubMed  CAS  Google Scholar 

  • Silverman N, Maniatis T (2001) NF-KB signaling pathways in mammalian and insect innate immunity. Genes Dev 15: 2321–2342

    Article  PubMed  CAS  Google Scholar 

  • Silverman N, Zhou R, Stoven S, Pandey N, Hultmark D, Maniatis T (2000) A Drosophila IKB kinase complex required for Relish cleavage and antibacterial immunity. Genes Dev 14: 2461–2471

    Article  PubMed  CAS  Google Scholar 

  • Sims JE, March CJ, Cosman D, Widmer MB, MacDonald HR, McMahan CJ, Grubin CE, Wignall JM, Jackson JL, Call SM, et al. (1988) cDNA expression cloning of the IL-1 receptor, a member of the immunoglobulin superfamily. Science 241:585–589

    Article  PubMed  CAS  Google Scholar 

  • Stoven S, Ando I, Kadalayil L, Engstrom Y, Hultmark D (2000) Activation of the Drosophila NF-KB factor Relish by rapid endoproteolytic cleavage. EMBO reports 1: 347–352

    Article  PubMed  CAS  Google Scholar 

  • Takeuchi O, Takeda K, Hoshino K, Adachi O, Ogawa T, Akira S (2000) Cellular responses to bacterial cell wall components are mediated through MyD88-dependent signaling cascades [In Process Citation]. Int Immunol 12: 113–117

    Article  PubMed  CAS  Google Scholar 

  • Tauszig S, Jouanguy E, Hoffmann JA, Imler JL (2000) Toll-related receptors and the control of antimicrobial peptide expression in Drosophila. Proc Natl Acad Sci USA 97: 10520–10525

    Article  PubMed  CAS  Google Scholar 

  • Tauszig-Delamasure S, Bilak H, Capovilla M, Hoffmann JA, Imler JL (2002) Drosophila MyD88 isrequired for the response to fungal and Gram-positive bacterial infections. Nat Immunol 3: 91–97

    Article  PubMed  CAS  Google Scholar 

  • Towb P, Bergmann A, Wasserman SA (2001) The protein kinase Pelle mediates feedback regulation in the Drosophila Toll signaling pathway. Development 128: 4729–4736

    PubMed  CAS  Google Scholar 

  • Tzou P, Ohresser S, Ferrandon D, Capovilla M, Reichhart JM, Lemaitre B, Hoffmann JA, Imler JL (2000) Tissue-specific inducible expression of antimicrobial peptide genes in Drosophila surface epithelia. Immunity 13: 737–748

    Article  PubMed  CAS  Google Scholar 

  • Uttenweiler-Joseph S, Moniatte M, Lagueux M, Van Dorsselaer A, Hoffmann JA, Bulet P (1998) Differential display of peptides induced during the immune response of Drosophila-. a matrix-assisted laser desorption ionization time-of- flight mass spectrometry study. Proc Natl Acad Sci USA 95: 11342–11347

    Article  PubMed  CAS  Google Scholar 

  • Vidal S, Khush RS, Leulier F, Tzou P, Nakamura M, Lemaitre B (2001) Mutations in the Drosophila dTAKl gene reveal a conserved function for MAPKKKs in the control of rel/NF-icB-dependent innate immune responses. Genes Dev 15: 1900–1912

    Article  PubMed  CAS  Google Scholar 

  • Werner T, Liu G, Kang D, Ekengren S, Steiner H, Hultmark D (2000) A family of peptidoglycan recognition proteins in the fruit fly Drosophila melanogaster. Proc Natl Acad Sci USA 97: 13772–13777

    Article  PubMed  CAS  Google Scholar 

  • Wesche H, Henzel WJ, Shillinglaw W, Li S, Cao Z (1997) MyD88: an adapter that recruits IRAK to the IL-1 receptor complex. Immunity 7: 837–847

    Article  PubMed  CAS  Google Scholar 

  • Williams M, Rodriguez A, Kimbrell D, Eldon E (1997) The 18-wheeler mutation reveals complex antibacterial gene regulation in Drosophila host defense. EMBO J 16: 6120–6130

    Article  PubMed  CAS  Google Scholar 

  • Xiao T, Towb P, Wasserman SA, Sprang SR (1999) Three-dimensional structure of a complex between the death domains of Pelle and Tube. Cell 99: 545–555

    Article  PubMed  CAS  Google Scholar 

  • Xu Y, Tao X, Shen B, Horng T, Medzhitov R, Manley JL, Tong L (2000) Structural basis for signal transduction by the Toll/interleukin-1 receptor domains. Nature 408: 111–115

    Article  PubMed  CAS  Google Scholar 

  • Zapata JM, Matsuzawa S, Godzik A, Leo E, Wasserman SA, and Reed JC (2000) The Drosophila tumor necrosis factor receptor-associated factor-1 (DTRAF1) interacts with Pelle and regulates NFKB activity. J Biol Chem 275: 12102–12107

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. UPR9022 du CNRS, Institut de Biologie Moléculaire et Cellulaire, 15 rue Descartes, 67000, Strasbourg, France

    J. L. Imler & J. A. Hoffmann

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  1. J. L. Imler
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  2. J. A. Hoffmann
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Editors and Affiliations

  1. Department of Immunology, The Scripps Research Institute, 10550 N. Torreye Pines Road, 92037, La Jolla, California, USA

    Bruce Beutler M.D.

  2. Institut für Medizinische Mikrobiologie, Immunologie and Hygiene Technische Universität München, Trogerstr. 9, 81675, München, Germany

    Hermann Wagner

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Imler, J.L., Hoffmann, J.A. (2002). Toll Receptors in Drosophila: a Family of Molecules Regulating Development and Immunity. In: Beutler, B., Wagner, H. (eds) Toll-Like Receptor Family Members and Their Ligands. Current Topics in Microbiology and Immunology, vol 270. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-59430-4_4

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  • DOI: https://doi.org/10.1007/978-3-642-59430-4_4

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