The Drosophila Toll Signaling Pathway

Journal of Immunology - Tập 186 Số 2 - Trang 649-656 - 2011
Susanna Valanne1, Jinghuan Wang1, Mika Rämet1,2
1*Laboratory of Experimental Immunology, Institute of Medical Technology, University of Tampere, 33014 Tampere, Finland; and
2†Department of Pediatrics, Tampere University Hospital, 33014 Tampere, Finland

Tóm tắt

Abstract The identification of the Drosophila melanogaster Toll pathway cascade and the subsequent characterization of TLRs have reshaped our understanding of the immune system. Ever since, Drosophila NF-κB signaling has been actively studied. In flies, the Toll receptors are essential for embryonic development and immunity. In total, nine Toll receptors are encoded in the Drosophila genome, including the Toll pathway receptor Toll. The induction of the Toll pathway by Gram-positive bacteria or fungi leads to the activation of cellular immunity as well as the systemic production of certain antimicrobial peptides. The Toll receptor is activated when the proteolytically cleaved ligand Spatzle binds to the receptor, eventually leading to the activation of the NF-κB factors Dorsal-related immunity factor or Dorsal. In this study, we review the current literature on the Toll pathway and compare the Drosophila and mammalian NF-κB pathways.

Từ khóa


Tài liệu tham khảo

Nüsslein-Volhard, 1980, Mutations affecting segment number and polarity in Drosophila., Nature, 287, 795, 10.1038/287795a0

Belvin, 1996, A conserved signaling pathway: the Drosophila toll-dorsal pathway., Annu. Rev. Cell Dev. Biol., 12, 393, 10.1146/annurev.cellbio.12.1.393

Sun, 1992, Cecropia immunoresponsive factor, an insect immunoresponsive factor with DNA-binding properties similar to nuclear-factor κ B., Eur. J. Biochem., 204, 885, 10.1111/j.1432-1033.1992.tb16708.x

Wasserman, 1993, A conserved signal transduction pathway regulating the activity of the rel-like proteins dorsal and NF-κ B., Mol. Biol. Cell, 4, 767, 10.1091/mbc.4.8.767

Rosetto, 1995, Signals from the IL-1 receptor homolog, Toll, can activate an immune response in a Drosophila hemocyte cell line., Biochem. Biophys. Res. Commun., 209, 111, 10.1006/bbrc.1995.1477

Taguchi, 1996, Chromosomal localization of TIL, a gene encoding a protein related to the Drosophila transmembrane receptor Toll, to human chromosome 4p14., Genomics, 32, 486, 10.1006/geno.1996.0150

Lemaitre, 1996, The dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in Drosophila adults., Cell, 86, 973, 10.1016/S0092-8674(00)80172-5

Medzhitov, 1997, A human homologue of the Drosophila Toll protein signals activation of adaptive immunity., Nature, 388, 394, 10.1038/41131

Rock, 1998, A family of human receptors structurally related to Drosophila Toll., Proc. Natl. Acad. Sci. USA, 95, 588, 10.1073/pnas.95.2.588

Kimbrell, 2001, The evolution and genetics of innate immunity., Nat. Rev. Genet., 2, 256, 10.1038/35066006

Halfon, 1995, The Drosophila toll gene functions zygotically and is necessary for proper motoneuron and muscle development., Dev. Biol., 169, 151, 10.1006/dbio.1995.1134

Qiu, 1998, A role for the Drosophila Toll/Cactus pathway in larval hematopoiesis., Development, 125, 1909, 10.1242/dev.125.10.1909

Hetru, 2009, NF-kappaB in the immune response of Drosophila., Cold Spring Harb. Perspect. Biol., 1, a000232, 10.1101/cshperspect.a000232

Aggarwal, 2008, Positive and negative regulation of the Drosophila immune response., BMB Rep., 41, 267, 10.5483/BMBRep.2008.41.4.267

Hultmark, 2003, Drosophila immunity: paths and patterns., Curr. Opin. Immunol., 15, 12, 10.1016/S0952-7915(02)00005-5

Zettervall, 2004, A directed screen for genes involved in Drosophila blood cell activation., Proc. Natl. Acad. Sci. USA, 101, 14192, 10.1073/pnas.0403789101

Lemaitre, 1995, Functional analysis and regulation of nuclear import of dorsal during the immune response in Drosophila., EMBO J., 14, 536, 10.1002/j.1460-2075.1995.tb07029.x

Sorrentino, 2004, Genetic analysis of contributions of dorsal group and JAK-Stat92E pathway genes to larval hemocyte concentration and the egg encapsulation response in Drosophila., Genetics, 166, 1343, 10.1534/genetics.166.3.1343

Bettencourt, 2004, Hemolymph-dependent and -independent responses in Drosophila immune tissue., J. Cell. Biochem., 92, 849, 10.1002/jcb.20123

Tang, 2008, A serpin that regulates immune melanization in the respiratory system of Drosophila., Dev. Cell, 15, 617, 10.1016/j.devcel.2008.08.017

Tauszig, 2000, Toll-related receptors and the control of antimicrobial peptide expression in Drosophila., Proc. Natl. Acad. Sci. USA, 97, 10520, 10.1073/pnas.180130797

Imler, 2001, Toll receptors in innate immunity., Trends Cell Biol., 11, 304, 10.1016/S0962-8924(01)02004-9

Imler, 2000, LPS-induced immune response in Drosophila., J. Endotoxin Res., 6, 459, 10.1177/09680519000060060801

Luo, 2001, Tehao functions in the Toll pathway in Drosophila melanogaster: possible roles in development and innate immunity., Insect Mol. Biol., 10, 457, 10.1046/j.0962-1075.2001.00284.x

Ooi, 2002, The Drosophila Toll-9 activates a constitutive antimicrobial defense., EMBO Rep., 3, 82, 10.1093/embo-reports/kvf004

Bettencourt, 2004, Toll and Toll-9 in Drosophila innate immune response., J. Endotoxin Res., 10, 261, 10.1177/09680519040100040101

Morisato, 1994, The spätzle gene encodes a component of the extracellular signaling pathway establishing the dorsal-ventral pattern of the Drosophila embryo., Cell, 76, 677, 10.1016/0092-8674(94)90507-X

Schneider, 1994, A processed form of the Spätzle protein defines dorsal-ventral polarity in the Drosophila embryo., Development, 120, 1243, 10.1242/dev.120.5.1243

Arnot, 2010, Molecular mechanism that induces activation of Spätzle, the ligand for the Drosophila Toll receptor., J. Biol. Chem., 285, 19502, 10.1074/jbc.M109.098186

Weber, 2007, Role of the Spatzle Pro-domain in the generation of an active toll receptor ligand., J. Biol. Chem., 282, 13522, 10.1074/jbc.M700068200

Weber, 2005, Ligand-receptor and receptor-receptor interactions act in concert to activate signaling in the Drosophila toll pathway., J. Biol. Chem., 280, 22793, 10.1074/jbc.M502074200

Gangloff, 2008, Structural insight into the mechanism of activation of the Toll receptor by the dimeric ligand Spätzle., J. Biol. Chem., 283, 14629, 10.1074/jbc.M800112200

DeLotto, 1998, Proteolytic processing of the Drosophila Spätzle protein by easter generates a dimeric NGF-like molecule with ventralising activity., Mech. Dev., 72, 141, 10.1016/S0925-4773(98)00024-0

Chasan, 1992, Activation of the easter zymogen is regulated by five other genes to define dorsal-ventral polarity in the Drosophila embryo., Development, 115, 607, 10.1242/dev.115.2.607

Hong, 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, 10.1016/0092-8674(95)90475-1

Cho, 2010, Pipe-dependent ventral processing of Easter by Snake is the defining step in Drosophila embryo DV axis formation., Curr. Biol., 20, 1133, 10.1016/j.cub.2010.04.056

Jang, 2006, A Spätzle-processing enzyme required for toll signaling activation in Drosophila innate immunity., Dev. Cell, 10, 45, 10.1016/j.devcel.2005.11.013

El Chamy, 2008, Sensing of ‘danger signals’ and pathogen-associated molecular patterns defines binary signaling pathways ‘upstream’ of Toll., Nat. Immunol., 9, 1165, 10.1038/ni.1643

Kambris, 2006, Drosophila immunity: a large-scale in vivo RNAi screen identifies five serine proteases required for Toll activation., Curr. Biol., 16, 808, 10.1016/j.cub.2006.03.020

Buchon, 2009, A single modular serine protease integrates signals from pattern-recognition receptors upstream of the Drosophila Toll pathway., Proc. Natl. Acad. Sci. USA, 106, 12442, 10.1073/pnas.0901924106

Gottar, 2006, Dual detection of fungal infections in Drosophila via recognition of glucans and sensing of virulence factors., Cell, 127, 1425, 10.1016/j.cell.2006.10.046

Sansonetti, 2006, The innate signaling of dangers and the dangers of innate signaling., Nat. Immunol., 7, 1237, 10.1038/ni1420

Matzinger, 2002, The danger model: a renewed sense of self., Science, 296, 301, 10.1126/science.1071059

Michel, 2001, Drosophila Toll is activated by Gram-positive bacteria through a circulating peptidoglycan recognition protein., Nature, 414, 756, 10.1038/414756a

Gobert, 2003, Dual activation of the Drosophila toll pathway by two pattern recognition receptors., Science, 302, 2126, 10.1126/science.1085432

Pili-Floury, 2004, In vivo RNA interference analysis reveals an unexpected role for GNBP1 in the defense against Gram-positive bacterial infection in Drosophila adults., J. Biol. Chem., 279, 12848, 10.1074/jbc.M313324200

Wang, 2006, Sensing of Gram-positive bacteria in Drosophila: GNBP1 is needed to process and present peptidoglycan to PGRP-SA., EMBO J., 25, 5005, 10.1038/sj.emboj.7601363

Bischoff, 2004, Function of the drosophila pattern-recognition receptor PGRP-SD in the detection of Gram-positive bacteria., Nat. Immunol., 5, 1175, 10.1038/ni1123

Leone, 2008, Crystal structure of Drosophila PGRP-SD suggests binding to DAP-type but not lysine-type peptidoglycan., Mol. Immunol., 45, 2521, 10.1016/j.molimm.2008.01.015

Horng, 2001, Drosophila MyD88 is an adapter in the Toll signaling pathway., Proc. Natl. Acad. Sci. USA, 98, 12654, 10.1073/pnas.231471798

Tauszig-Delamasure, 2002, Drosophila MyD88 is required for the response to fungal and Gram-positive bacterial infections., Nat. Immunol., 3, 91, 10.1038/ni747

Sun, 2002, A heterotrimeric death domain complex in Toll signaling., Proc. Natl. Acad. Sci. USA, 99, 12871, 10.1073/pnas.202396399

Xiao, 1999, Three-dimensional structure of a complex between the death domains of Pelle and Tube., Cell, 99, 545, 10.1016/S0092-8674(00)81542-1

Moncrieffe, 2008, Assembly of oligomeric death domain complexes during Toll receptor signaling., J. Biol. Chem., 283, 33447, 10.1074/jbc.M805427200

Haghayeghi, 2010, Pellino enhances innate immunity in Drosophila., Mech. Dev., 127, 301, 10.1016/j.mod.2010.01.004

Moynagh, 2009, The Pellino family: IRAK E3 ligases with emerging roles in innate immune signalling., Trends Immunol., 30, 33, 10.1016/j.it.2008.10.001

Wu, 1998, Regulated nuclear import of Rel proteins in the Drosophila immune response., Nature, 392, 93, 10.1038/32195

Towb, 2001, The protein kinase Pelle mediates feedback regulation in the Drosophila Toll signaling pathway., Development, 128, 4729, 10.1242/dev.128.23.4729

Huang, 2010, Endocytic pathway is required for Drosophila Toll innate immune signaling., Proc. Natl. Acad. Sci. USA, 107, 8322, 10.1073/pnas.1004031107

Fernandez, 2001, Separable and redundant regulatory determinants in Cactus mediate its dorsal group dependent degradation., Development, 128, 2963, 10.1242/dev.128.15.2963

Lu, 2001, The antibacterial arm of the drosophila innate immune response requires an IkappaB kinase., Genes Dev., 15, 104, 10.1101/gad.856901

Rutschmann, 2000, Role of Drosophila IKK γ in a toll-independent antibacterial immune response., Nat. Immunol., 1, 342, 10.1038/79801

Reichhart, 1993, Expression and nuclear translocation of the rel/NF-κ B-related morphogen dorsal during the immune response of Drosophila., C. R. Acad. Sci. III, 316, 1218

Kidd, 1992, Characterization of the Drosophila cactus locus and analysis of interactions between cactus and dorsal proteins., Cell, 71, 623, 10.1016/0092-8674(92)90596-5

Yang, 1997, A multimeric complex and the nuclear targeting of the Drosophila Rel protein Dorsal., Proc. Natl. Acad. Sci. USA, 94, 14524, 10.1073/pnas.94.26.14524

Edwards, 1997, An activity-dependent network of interactions links the Rel protein Dorsal with its cytoplasmic regulators., Development, 124, 3855, 10.1242/dev.124.19.3855

Gross, 1996, Drosophila immunity: a comparative analysis of the Rel proteins dorsal and Dif in the induction of the genes encoding diptericin and cecropin., Nucleic Acids Res., 24, 1238, 10.1093/nar/24.7.1238

Lau, 2003, The Drosophila melanogaster toll pathway participates in resistance to infection by the gram-negative human pathogen Pseudomonas aeruginosa., Infect. Immun., 71, 4059, 10.1128/IAI.71.7.4059-4066.2003

Ip, 1993, Dif, a dorsal-related gene that mediates an immune response in Drosophila., Cell, 75, 753, 10.1016/0092-8674(93)90495-C

Tatei, 1995, Specificity of Rel-inhibitor interactions in Drosophila embryos., Mol. Cell. Biol., 15, 3627, 10.1128/MCB.15.7.3627

Rutschmann, 2000, The Rel protein DIF mediates the antifungal but not the antibacterial host defense in Drosophila., Immunity, 12, 569, 10.1016/S1074-7613(00)80208-3

Manfruelli, 1999, A mosaic analysis in Drosophila fat body cells of the control of antimicrobial peptide genes by the Rel proteins Dorsal and DIF., EMBO J., 18, 3380, 10.1093/emboj/18.12.3380

Valanne, 2010, Genome-wide RNA interference in Drosophila cells identifies G protein-coupled receptor kinase 2 as a conserved regulator of NF-kappaB signaling., J. Immunol., 184, 6188, 10.4049/jimmunol.1000261

Rämet, 2002, Functional genomic analysis of phagocytosis and identification of a Drosophila receptor for E. coli., Nature, 416, 644, 10.1038/nature735

Boutros, 2004, Genome-wide RNAi analysis of growth and viability in Drosophila cells., Science, 303, 832, 10.1126/science.1091266

Ulvila, 2006, Double-stranded RNA is internalized by scavenger receptor-mediated endocytosis in Drosophila S2 cells., J. Biol. Chem., 281, 14370, 10.1074/jbc.M513868200

Saleh, 2006, The endocytic pathway mediates cell entry of dsRNA to induce RNAi silencing., Nat. Cell Biol., 8, 793, 10.1038/ncb1439

Reed, 2008, DEAF-1 regulates immunity gene expression in Drosophila., Proc. Natl. Acad. Sci. USA, 105, 8351, 10.1073/pnas.0802921105

Kuttenkeuler, 2010, A large-scale RNAi screen identifies Deaf1 as a regulator of innate immune responses in Drosophila., J. Innate Immun., 2, 181, 10.1159/000248649

Lemaitre, 2007, The host defense of Drosophila melanogaster., Annu. Rev. Immunol., 25, 697, 10.1146/annurev.immunol.25.022106.141615

Choe, 2002, Requirement for a peptidoglycan recognition protein (PGRP) in Relish activation and antibacterial immune responses in Drosophila., Science, 296, 359, 10.1126/science.1070216

Hedengren, 1999, Relish, a central factor in the control of humoral but not cellular immunity in Drosophila., Mol. Cell, 4, 827, 10.1016/S1097-2765(00)80392-5

Dushay, 1996, Origins of immunity: Relish, a compound Rel-like gene in the antibacterial defense of Drosophila., Proc. Natl. Acad. Sci. USA, 93, 10343, 10.1073/pnas.93.19.10343

Silverman, 2000, A Drosophila IkappaB kinase complex required for Relish cleavage and antibacterial immunity., Genes Dev., 14, 2461, 10.1101/gad.817800

Lemaitre, 1997, Drosophila host defense: differential induction of antimicrobial peptide genes after infection by various classes of microorganisms., Proc. Natl. Acad. Sci. USA, 94, 14614, 10.1073/pnas.94.26.14614

Kleino, 2005, Inhibitor of apoptosis 2 and TAK1-binding protein are components of the Drosophila Imd pathway., EMBO J., 24, 3423, 10.1038/sj.emboj.7600807

Tanji, 2007, Toll and IMD pathways synergistically activate an innate immune response in Drosophila melanogaster., Mol. Cell. Biol., 27, 4578, 10.1128/MCB.01814-06

De Gregorio, 2002, The Toll and Imd pathways are the major regulators of the immune response in Drosophila., EMBO J., 21, 2568, 10.1093/emboj/21.11.2568

Han, 1999, Interaction and specificity of Rel-related proteins in regulating Drosophila immunity gene expression., J. Biol. Chem., 274, 21355, 10.1074/jbc.274.30.21355

Rutschmann, 2002, Cutting edge: the toll pathway is required for resistance to gram-positive bacterial infections in Drosophila., J. Immunol., 168, 1542, 10.4049/jimmunol.168.4.1542

Engström, 1993, kappaB-like motifs regulate the induction of immune genes in Drosophila., J. Mol. Biol., 232, 327, 10.1006/jmbi.1993.1392

Petersen, 1999, Serpent regulates Drosophila immunity genes in the larval fat body through an essential GATA motif., EMBO J., 18, 4013, 10.1093/emboj/18.14.4013

Senger, 2006, GATA factors participate in tissue-specific immune responses in Drosophila larvae., Proc. Natl. Acad. Sci. USA, 103, 15957, 10.1073/pnas.0607608103

Poltorak, 1998, Genetic and physical mapping of the Lps locus: identification of the toll-4 receptor as a candidate gene in the critical region., Blood Cells Mol. Dis., 24, 340, 10.1006/bcmd.1998.0201

Takeuchi, 2010, Pattern recognition receptors and inflammation., Cell, 140, 805, 10.1016/j.cell.2010.01.022

Towb, 2009, Tube Is an IRAK-4 homolog in a Toll pathway adapted for development and immunity., J. Innate Immun., 1, 309, 10.1159/000200773

Dunne, 2003, Structural complementarity of Toll/interleukin-1 receptor domains in Toll-like receptors and the adaptors Mal and MyD88., J. Biol. Chem., 278, 41443, 10.1074/jbc.M301742200

Lin, 2010, Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-1R signalling., Nature, 465, 885, 10.1038/nature09121

Silverman, 2001, NF-kappaB signaling pathways in mammalian and insect innate immunity., Genes Dev., 15, 2321, 10.1101/gad.909001

Leulier, 2000, The Drosophila caspase Dredd is required to resist gram-negative bacterial infection., EMBO Rep., 1, 353, 10.1093/embo-reports/kvd073

Paquette, 2010, Caspase-mediated cleavage, IAP binding, and ubiquitination: linking three mechanisms crucial for Drosophila NF-kappaB signaling., Mol. Cell, 37, 172, 10.1016/j.molcel.2009.12.036

Patial, 2010, G-protein-coupled-receptor kinases mediate TNFα-induced NF-κB signalling via direct interaction with and phosphorylation of IkBα., Biochem. J., 425, 169, 10.1042/BJ20090908

Patial, 2010, G-protein coupled receptor kinase 5 mediates lipopolysaccharide-induced NFκB activation in primary macrophages and modulates inflammation in vivo in mice., J. Cell. Physiol.

Kawai, 2006, TLR signaling., Cell Death Differ., 13, 816, 10.1038/sj.cdd.4401850

Goto, 2008, Akirins are highly conserved nuclear proteins required for NF-kappaB-dependent gene expression in drosophila and mice., Nat. Immunol., 9, 97, 10.1038/ni1543

Kleino, 2008, Pirk is a negative regulator of the Drosophila Imd pathway., J. Immunol., 180, 5413, 10.4049/jimmunol.180.8.5413

Kim, 2006, Caspar, a suppressor of antibacterial immunity in Drosophila., Proc. Natl. Acad. Sci. USA, 103, 16358, 10.1073/pnas.0603238103

Foley, 2004, Functional dissection of an innate immune response by a genome-wide RNAi screen., PLoS Biol., 2, E203, 10.1371/journal.pbio.0020203