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Interleukin-1 Receptor/Toll-Like Receptor Signaling

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Toll and Toll-Like Receptors: An Immunologic Perspective

Part of the book series: Molecular Biology Intelligence Unit ((MBIU))

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Abstract

Upon stimulation Interleukin-1 receptor (IL-1R), the related IL-18R as well as the Toll-like receptors (TLRs), trigger signaling pathways that activate the transcription factors, nuclear factor κB (NF-κB), activator protein 1 (AP1) and interferon regulatory factor 3 (IRF-3). All members of the IL-1R/TLR family commonly induce NF-κB and AP1 whereas IRF-3 is targeted specifically by TLR3 and TLR4. While IRF-3 activation has only recently been recognized, NF-kB and AP1 activation, in particular by IL-1R, has been intensively studied. Indeed, most of the molecular components that transduce the IL-1R signal to activate NF-κB have been identified. There is considerable evidence that these proteins are also relevant to TLR signaling. Although there is, in some aspects, a very detailed understanding of how the various signaling proteins coordinate to achieve IL-1R driven NF-κB activation there are still gaps in the overall picture. The following chapter aims to give a comprehensive review on IL-1R/TLR signaling, focusing on the similarities and differences between these pathways in humans and in Drosophila. To facilitate a proper discussion of the molecular mechanisms involved in IL-1R/TLR signaling the relevant proteins will be introduced before IL-1R signaling in mammals and Toll signaling in flies are discussed in detail.

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References

  1. Silverman N, Maniatis T. NF-kappaB signaling pathways in mammalian and insect innate immunity. Genes Dev 2001; 15:2321–2342.

    PubMed  CAS  Google Scholar 

  2. Barton GM, Medzhitov R. Toll-like receptors and their ligands. Curr Top Microbiol Immunol 2002; 270:81–92.

    PubMed  CAS  Google Scholar 

  3. Dunne A, O’Neill LAJ. The Interleukin-1 Receptor/Toll-Like Receptor Superfamily: Signal Transduction During Inflammation and Host Defense. Sci STKE 2003; re3.

    Google Scholar 

  4. Lord KA, Hoffman-Liebermann B, Liebermann DA. Nucleotide sequence and expression of a cDNA encoding MyD88, a novel myeloid differentiation primary response gene induced by IL6. Oncogene 1990; 5:1095–1097.

    PubMed  CAS  Google Scholar 

  5. Fitzgerald KA, Palsson-McDermott EM, Bowie AG et al. Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction. Nature 2001; 413:78–83.

    PubMed  CAS  Google Scholar 

  6. Horng T, Barton GM, Medzhitov R. TIRAP: An adapter molecule in the Toll signaling pathway. Nat Immunol 2001; 2:835–841.

    PubMed  CAS  Google Scholar 

  7. Oshiumi H, Matsumoto M, Funami K et al. TICAM-1, an adaptor molecule that participates in Toll-like receptor 3-mediated interferon-beta induction. Nat Immunol 2003; 4:161–167.

    PubMed  CAS  Google Scholar 

  8. Yamamoto M, Sato S, Mori K et al. Cutting edge: A novel Toll/IL-1 receptor domain-containing adapter that preferentially activates the IFN-beta promoter in the Toll-like receptor signaling. J Immunol 2002; 169:6668–6672.

    PubMed  CAS  Google Scholar 

  9. Tauszig-Delamasure S, Bilak H, Capovilla M et al. Drosophila MyD88 is required for the response to fungal and Gram-positive bacterial infections. Nat Immunol 2002; 3:91–97.

    PubMed  CAS  Google Scholar 

  10. urns K, Martinon F, Esslinger C et al. MyD88, an adapter protein involved in interleukin-1 signaling. J Biol Chem 1998; 273:12203–12209.

    Google Scholar 

  11. Shelton CA, Wasserman SA. Pelle encodes a protein kinase required to establish dorsoventral polarity in the Drosophila embryo. Cell 1993; 72:515–525.

    PubMed  CAS  Google Scholar 

  12. Cao Z, Henzel WJ, Gao X. IRAK: A kinase associated with the interleukin-1 receptor. Science 1996; 271:1128–1131.

    PubMed  CAS  Google Scholar 

  13. Muzio M, Ni J, Feng P et al. IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling. Science 1997; 278:1612–1615.

    PubMed  CAS  Google Scholar 

  14. Wesche H, Gao X, Li X et al. IRAK-M is a novel member of the Pelle/interleukin-1 receptor-associated kinase (IRAK) family. J Biol Chem 1999; 274:19403–19410.

    PubMed  CAS  Google Scholar 

  15. Li S, Strelow A, Fontana EJ et al. IRAK-4: A novel member of the IRAK family with the properties of an IRAK-kinase. Proc Natl Acad Sci USA 2002; 99:5567–5572.

    PubMed  CAS  Google Scholar 

  16. Suzuki N, Suzuki S, Duncan GS et al. Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4. Nature 2002; 416:750–756.

    PubMed  CAS  Google Scholar 

  17. Wajant H, Henkler F, Scheurich P. The TNF-receptor-associated factor family: Scaffold molecules for cytokine receptors, kinases and their regulators. Cell Signal 2001; 13:389–400.

    PubMed  CAS  Google Scholar 

  18. Rothe M, Wong SC, Henzel WJ et al. A novel family of putative signal transducers associated with the cytoplasmic domain of the 75 kDa tumor necrosis factor receptor. Cell 1994; 78:681–692.

    PubMed  CAS  Google Scholar 

  19. Grech A, Quinn R, Srinivasan D et al. Complete structural characterisation of the mammalian and Drosophila TRAF genes: Implications for TRAF evolution and the role of RING finger splice variants. Mol Immunol 2000; 37:721–734.

    PubMed  CAS  Google Scholar 

  20. Park YC, Burkitt V, Villa AR et al. Structural basis for self-association and receptor recognition of human TRAF2. Nature 1999; 398:533–538.

    PubMed  CAS  Google Scholar 

  21. McWhirter SM, Pullen SS, Holton JM et al. Crystallographic analysis of CD40 recognition and signaling by human TRAF2. Proc Natl Acad Sci USA 1999; 96:8408–8413.

    PubMed  CAS  Google Scholar 

  22. Ni CZ, Welsh K, Leo E et al. Molecular basis for CD40 signaling mediated by TRAF3. Proc Natl Acad Sci USA 2000; 97:10395–10399.

    PubMed  CAS  Google Scholar 

  23. Ye H, Arron JR, Lamothe B et al. Distinct molecular mechanism for initiating TRAF6 signalling. Nature 2002; 418:443–447.

    PubMed  CAS  Google Scholar 

  24. Ye H, Wu H. Thermodynamic characterization of the interaction between TRAF2 and tumor necrosis factor receptor peptides by isothermal titration calorimetry. Proc Natl Acad Sci USA 2000; 97:8961–8966.

    PubMed  CAS  Google Scholar 

  25. Hsu H, Shu HB, Pan MG et al. TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways. Cell 1996; 84:299–308.

    PubMed  CAS  Google Scholar 

  26. Karin M, Lin A. NF-kappaB at the crossroads of life and death. Nat Immunol 2002; 3:221–227.

    PubMed  CAS  Google Scholar 

  27. Rothwarf DM, Karin M. The NF-kappa B activation pathway: A paradigm in information transfer from membrane to nucleus. Sci STKE 1999; 1999:RE1.

    PubMed  CAS  Google Scholar 

  28. Stoven S, Ando I, Kadalayil L et al. Activation of the Drosophila NF-kappaB factor Relish by rapid endoproteolytic cleavage. EMBO Rep 2000; 1:347–352.

    PubMed  CAS  Google Scholar 

  29. Leulier F, Rodriguez A, Khush RS et al. The Drosophila caspase Dredd is required to resist gram-negative bacterial infection. EMBO Rep 2000; 1:353–358.

    PubMed  CAS  Google Scholar 

  30. Chen G, Cao P, Goeddel DV. TNF-induced recruitment and activation of the IKK complex require Cdc37 and Hsp90. Mol Cell 2002; 9:401–410.

    PubMed  CAS  Google Scholar 

  31. Greenfeder SA, Nunes P, Kwee L et al. Molecular cloning and characterization of a second subunit of the interleukin 1 receptor complex. J Biol Chem 1995; 270:13757–13765.

    PubMed  CAS  Google Scholar 

  32. Huang J, Gao X, Li S et al. Recruitment of IRAK to the interleukin 1 receptor complex requires interleukin 1 receptor accessory protein. Proc Natl Acad Sci USA 1997; 94:12829–12832.

    PubMed  CAS  Google Scholar 

  33. Korherr C, Hofmeister R, Wesche H et al. A critical role for interleukin-1 receptor accessory protein in interleukin-1 signaling. Eur J Immunol 1997; 27:262–267.

    PubMed  CAS  Google Scholar 

  34. Wesche H, Henzel WJ, Shillinglaw W et al. MyD88: An adapter that recruits IRAK to the IL-1 receptor complex. Immunity 1997; 7:837–847.

    PubMed  CAS  Google Scholar 

  35. Burns K, Clatworthy J, Martin L et al. Tollip, a new component of the IL-1R pathway, links IRAK to the IL-1 receptor. Nat Cell Biol 2000; 2:346–351.

    PubMed  CAS  Google Scholar 

  36. Yamin TT, Miller DK. The interleukin-1 receptor-associated kinase is degraded by proteasomes following its phosphorylation. J Biol Chem 1997; 272:21540–21547.

    PubMed  CAS  Google Scholar 

  37. Jiang Z, Ninomiya-Tsuji J, Qian Y et al. Interleukin-1 (IL-1) receptor-associated kinase-dependent IL-1-induced signaling complexes phosphorylate TAK1 and TAB2 at the plasma membrane and activate TAK1 in the cytosol. Mol Cell Biol 2002; 22:7158–7167.

    PubMed  CAS  Google Scholar 

  38. Qian Y, Commane M, Ninomiya-Tsuji J et al. IRAK-mediated translocation of TRAF6 and TAB2 in the interleukin-1-induced activation of NF-kappaB. J Biol Chem 2001; 276:41661–41667.

    PubMed  CAS  Google Scholar 

  39. Zhang G, Ghosh S. Negative regulation of Toll-like receptor-mediated signaling by Tollip. J Biol Chem 2002; 277:7059–7065.

    PubMed  CAS  Google Scholar 

  40. Jiang Z, Johnson HJ, Nie H et al. Pellino 1 is required for IL-1-mediated signaling through its interaction with IRAK4-IRAK-TRAF6. J Biol Chem 2002; 278:10952–10956

    PubMed  Google Scholar 

  41. Yamaguchi K, Shirakabe K, Shibuya H et al. Identification of a member of the MAPKKK family as a potential mediator of TGF-beta signal transduction. Science 1995; 270:2008–2011.

    PubMed  CAS  Google Scholar 

  42. Shibuya H, Yamaguchi K, Shirakabe K et al. TAB1: An activator of the TAK1 MAPKKK in TGF-beta signal transduction. Science 1996; 272:1179–1182.

    PubMed  CAS  Google Scholar 

  43. Takaesu G, Kishida S, Hiyama A et al. TAB2, a novel adaptor protein, mediates activation of TAK1 MAPKKK by linking TAK1 to TRAF6 in the IL-1 signal transduction pathway. Mol Cell 2000; 5:649–658.

    PubMed  CAS  Google Scholar 

  44. Deng L, Wang C, Spencer E et al. Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Cell 2000; 103:351–361.

    PubMed  CAS  Google Scholar 

  45. Wang C, Deng L, Hong M et al. TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature 2001; 412:346–351.

    PubMed  CAS  Google Scholar 

  46. Takaesu G, Surabhi RM, Park KJ et al. TAK1 is critical for IkappaB Kinase-mediated activation of the NF-kappaB pathway. J Mol Biol 2003; 326:105–115.

    PubMed  CAS  Google Scholar 

  47. Lee FS, Peters RT, Dang LC et al. MEKK1 activates both IkappaB kinase alpha and IkappaB kinase beta. Proc Natl Acad Sci USA 1998; 95:9319–9324.

    PubMed  CAS  Google Scholar 

  48. Zhao Q, Lee FS. Mitogen-activated protein kinase/ERK kinase kinases 2 and 3 activate nuclear factor-kappaB through IkappaB kinase-alpha and IkappaB kinase-beta. J Biol Chem 1999; 274:8355–8358.

    PubMed  CAS  Google Scholar 

  49. Malinin NL, Boldin MP, Kovalenko AV et al. MAP3K-related kinase involved in NF-kappaB induction by TNF, CD95 and IL-1. Nature 1997; 385:540–544.

    PubMed  CAS  Google Scholar 

  50. Yin L, Wu L, Wesche H et al. Defective lymphotoxin-beta receptor-induced NF-kappaB transcriptional activity in NIK-deficient mice. Science 2001; 291:2162–2165.

    PubMed  CAS  Google Scholar 

  51. Yujiri T, Ware M, Widmann C et al. MEK kinase 1 gene disruption alters cell migration and c-Jun NH2-terminal kinase regulation but does not cause a measurable defect in NF-kappa B activation. Proc Natl Acad Sci USA 2000; 97:7272–7277.

    PubMed  CAS  Google Scholar 

  52. Yang J, Lin Y, Guo Z et al. The essential role of MEKK3 in TNF-induced NF-kappaB activation. Nat Immunol 2001; 2:620–624.

    PubMed  CAS  Google Scholar 

  53. Sanjo H, Takeda K, Tsujimura T et al. TAB2 is essential for prevention of apoptosis in fetal liver but not for interleukin-1 signaling. Mol Cell Biol 2003; 23:1231–1238.

    PubMed  CAS  Google Scholar 

  54. Munoz-Sanjuan I, Bell E, Altmann CR et al. Gene profiling during neural induction in Xenopus laevis: Regulation of BMP signaling by post-transcriptional mechanisms and TAB3, a novel TAKl-binding protein. Development 2002; 129:5529–5540.

    PubMed  CAS  Google Scholar 

  55. Lallena MJ, Diaz-Meco MT, Bren G et al. Activation of IkappaB kinase beta by protein kinase C isoforms. Mol Cell Biol 1999; 19:2180–2188.

    PubMed  CAS  Google Scholar 

  56. Sanz L, Sanchez P, Lallena MJ et al. The interaction of p62 with RIP links the atypical PKCs to NF-kappaB activation. EMBO J 1999; 18:3044–3053.

    PubMed  CAS  Google Scholar 

  57. Vadlamudi RK, Joung I, Strominger JL et al. p62, a phosphotyrosine-independent ligand of the SH2 domain of p561ck, belongs to a new class of ubiquitin-binding proteins. J Biol Chem 1996; 271:20235–20237.

    PubMed  CAS  Google Scholar 

  58. Leitges M, Sanz L, Martin P et al. Targeted disruption of the zetaPKC gene results in the impairment of the NF-kappaB pathway. Mol Cell 2001; 8:771–780.

    PubMed  CAS  Google Scholar 

  59. Schmidt-Supprian M, Bloch W, Courtois G et al. NEMO/IKK gamma-deficient mice model incontinentia pigmenti. Mol Cell 2000; 5:981–992.

    PubMed  CAS  Google Scholar 

  60. Rudolph D, Yeh WC, Wakeham A et al. Severe liver degeneration and lack of NF-kappaB activation in NEMO/IKKgamma-deficient mice. Genes Dev 2000; 14:854–862.

    PubMed  CAS  Google Scholar 

  61. Makris C, Godfrey VL, Krahn-Senftleben G et al. Female mice heterozygous for IKK gamma/NEMO deficiencies develop a dermatopathy similar to the human X-linked disorder incontinentia pigmenti. Mol Cell 2000; 5:969–979.

    PubMed  CAS  Google Scholar 

  62. Li Q, Estepa G, Memet S et al. Complete lack of NF-kappaB activity in IKK1 and IKK2 double-deficient mice: Additional defect in neurulation. Genes Dev 2000; 14:1729–1733.

    PubMed  CAS  Google Scholar 

  63. Li Q, Van Antwerp D, Mercurio F et al. Severe liver degeneration in mice lacking the IkappaB kinase 2 gene. Science 1999; 284:321–325.

    PubMed  CAS  Google Scholar 

  64. Tanaka M, Fuentes ME, Yamaguchi K et al. Embryonic lethality, liver degeneration, and impaired NF-kappaB activation in IKK-beta-deficient mice. Immunity 1999; 10:421–429.

    PubMed  CAS  Google Scholar 

  65. Sizemore N, Lerner N, Dombrowski N et al. Distinct roles of the Ikappa B kinase alpha and beta subunits in liberating nuclear factor kappa B (NF-kappa B) from Ikappa B and in phosphorylating the p65 subunit of NF-kappaB. J Biol Chem 2002; 277:3863–3869.

    PubMed  CAS  Google Scholar 

  66. Li Q, Lu Q, Hwang JY et al. IKK1-deficient mice exhibit abnormal development of skin and skeleton. Genes Dev 1999; 13:1322–1328.

    PubMed  CAS  Google Scholar 

  67. Takeda K, Takeuchi O, Tsujimura T et al. Limb and skin abnormalities in mice lacking IKKalpha. Science 1999; 284:313–316.

    PubMed  CAS  Google Scholar 

  68. Shaulian E, Karin M. AP-1 as a regulator of cell life and death. Nat Cell Biol 2002; 4:E131–E136.

    PubMed  CAS  Google Scholar 

  69. Chen W, White MA, Cobb MH. Stimulus-specific requirements for MAP3 kinases in activating the JNK pathway. J Biol Chem 2002; 277:49105–49110.

    PubMed  CAS  Google Scholar 

  70. Li X, Commane M, Jiang Z et al. IL-1-induced NFkappa B and c-Jun N-terminal kinase (JNK) activation diverge at IL-1 receptor-associated kinase (IRAK). Proc Natl Acad Sci USA 2001; 98:4461–4465.

    PubMed  CAS  Google Scholar 

  71. McDermott EP, O’Neill LA. Ras participates in the activation of p38 MAPK by interleukin-1 by associating with IRAK, IRAK2, TRAF6, and TAK-1. J Biol Chem 2002; 277:7808–7815.

    PubMed  CAS  Google Scholar 

  72. Ge B, Gram H, Di Padova F et al. MAPKK-independent activation of p38alpha mediated by TAB1-dependent autophosphorylation of p38alpha. Science 2002; 295:1291–1294.

    PubMed  CAS  Google Scholar 

  73. Adachi O, Kawai T, Takeda K et al. Targeted disruption of the MyD88 gene results in loss of IL-1-and IL-18-mediated function. Immunity 1998; 9:143–150.

    PubMed  CAS  Google Scholar 

  74. Hacker H, Vabulas RM, Takeuchi O et al. Immune cell activation by bacterial CpG-DNA through myeloid differentiation marker 88 and tumor necrosis factor receptor-associated factor (TRAF)6. J Exp Med 2000; 192:595–600.

    PubMed  CAS  Google Scholar 

  75. Kawai T, Adachi O, Ogawa T et al. Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity 1999; 11:115–122.

    PubMed  CAS  Google Scholar 

  76. Hemmi H, Takeuchi O, Kawai T et al. A Toll-like receptor recognizes bacterial DNA. Nature 2000; 408:740–745.

    PubMed  CAS  Google Scholar 

  77. Hayashi F, Smith KD, Ozinsky A et al. The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 2001; 410:1099–1103.

    PubMed  CAS  Google Scholar 

  78. Hemmi H, Kaisho T, Takeuchi O et al. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol 2002; 3:196–200

    PubMed  CAS  Google Scholar 

  79. Kanakaraj P, Schafer PH, Cavender DE et al. Interleukin (IL)-1 receptor-associated kinase (IRAK) requirement for optimal induction of multiple IL-1 signaling pathways and IL-6 production. J Exp Med 1998; 187:2073–2079.

    PubMed  CAS  Google Scholar 

  80. Kanakaraj P, Ngo K, Wu Y et al. Defective interleukin (IL)-18-mediated natural killer and T helper cell type 1 responses in IL-1 receptor-associated kinase (IRAK)-deficient mice. J Exp Med 1999; 189:1129–1138.

    PubMed  CAS  Google Scholar 

  81. Thomas JA, Allen JL, Tsen M et al. Impaired cytokine signaling in mice lacking the IL-1 receptor-associated kinase. J Immunol 1999; 163:978–984.

    PubMed  CAS  Google Scholar 

  82. Lomaga MA, Yeh WC, Sarosi I et al. TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling. Genes Dev 1999; 13:1015–1024.

    PubMed  CAS  Google Scholar 

  83. Naito A, Azuma S, Tanaka S et al. Severe osteopetrosis, defective interleukin-1 signalling and lymph node organogenesis in TRAF6-deficient mice. Genes Cells 1999; 4:353–362.

    PubMed  CAS  Google Scholar 

  84. Kaisho T, Takeuchi O, Kawai T et al. Endotoxin-induced maturation of MyD88-deficient dendritic cells. J Immunol 2001; 166:5688–5694.

    PubMed  CAS  Google Scholar 

  85. Alexopoulou L, Holt AC, Medzhitov R et al. Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature 2001; 413:732–738.

    PubMed  CAS  Google Scholar 

  86. Yamamoto M, Sato S, Hemmi H et al. Essential role for TIRAP in activation of the signaling cascade shared by TLR2 and TLR4. Nature 2002; 420:324–329.

    PubMed  CAS  Google Scholar 

  87. Goh KC, deVeer MJ, Williams BR. The protein kinase PKR is required for p38 MAPK activation and the innate immune response to bacterial endotoxin. EMBO J 2000; 19:4292–4297.

    PubMed  CAS  Google Scholar 

  88. Burkle A. PARP-1: A regulator of genomic stability linked with mammalian longevity. Chembiochem 2001; 2:725–728.

    PubMed  CAS  Google Scholar 

  89. Hassa PO, Hottiger MO. The functional role of poly(ADP-ribose)polymerase 1 as novel coactivator of NF-kappaB in inflammatory disorders. Cell Mol Life Sci 2002; 59:1534–1553.

    PubMed  CAS  Google Scholar 

  90. Oliver FJ, Menissier-de Murcia J, Nacci C et al. Resistance to endotoxic shock as a consequence of defective NF-kappaB activation in poly (ADP-ribose) polymerase-1 deficient mice. EMBO J 1999; 18:4446–4454.

    PubMed  CAS  Google Scholar 

  91. Hassa PO, Hottiger MO. A role of poly (ADP-ribose) polymerase in NF-kappaB transcriptional activation. Biol Chem 1999; 380:953–959.

    PubMed  CAS  Google Scholar 

  92. Van Heel DA, McGovern DP, Jewell DP. Crohn’s disease: Genetic susceptibility, bacteria, and innate immunity. Lancet 2001; 357:1902–1904.

    PubMed  Google Scholar 

  93. Krikos A, Laherty CD, Dixit VM. Transcriptional activation of the tumor necrosis factor alpha-inducible zinc finger protein, A20, is mediated by kappa B elements. J Biol Chem 1992; 267:17971–17976.

    PubMed  CAS  Google Scholar 

  94. Janssens S, Burns K, Tschopp J et al. Regulation of interleukin-1-and lipopolysaccharide-induced NF-kappaB activation by alternative splicing of MyD88. Curr Biol 2002; 12:467–471.

    PubMed  CAS  Google Scholar 

  95. Kobayashi K, Hernandez LD, Galan JE et al. IRAK-M is a negative regulator of Toll-like receptor signaling. Cell 2002; 110:191–202.

    PubMed  CAS  Google Scholar 

  96. Burns K, Janssens S, Brissoni B et al. Inhibition of Interleukin 1 Receptor/Toll-like receptor signaling through the alternatively spliced, short form of MyD88 Is due to its failure to recruit IRAK-4. J Exp Med 2003; 197:263–268.

    PubMed  Google Scholar 

  97. Song HY, Rothe M, Goeddel DV. The tumor necrosis factor-inducible zinc finger protein A20 interacts with TRAF1/TRAF2 and inhibits NF-kappaB activation. Proc Natl Acad Sci USA 1996; 93:6721–6725.

    PubMed  CAS  Google Scholar 

  98. Heyninck K, Beyaert R. The cytokine-inducible zinc finger protein A20 inhibits IL-1-induced NF-kappaB activation at the level of TRAF6. FEBS Lett 1999; 442:147–150.

    PubMed  CAS  Google Scholar 

  99. Zhang SQ, Kovalenko A, Cantarella G et al. Recruitment of the IKK signalosome to the p55 TNF receptor: RIP and A20 bind to NEMO (IKKgamma) upon receptor stimulation. Immunity 2000; 12:301–311.

    PubMed  CAS  Google Scholar 

  100. Lee EG, Boone DL, Chai S et al. Failure to regulate TNF-induced NF-kappaB and cell death responses in A20-deficient mice. Science 2000; 289:2350–2354.

    PubMed  CAS  Google Scholar 

  101. He KL, Ting AT. A20 inhibits tumor necrosis factor (TNF) alpha-induced apoptosis by disrupting recruitment of TRADD and RIP to the TNF receptor 1 complex in Jurkat T cells. Mol Cell Biol 2002; 22:6034–6045.

    PubMed  CAS  Google Scholar 

  102. Belvin MP, Anderson KV. A conserved signaling pathway: The Drosophila Toll-dorsal pathway. Annu Rev Cell Dev Biol 1996; 12:393–416.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  106. Levashina EA, Langley E, Green C et al. Constitutive activation of Toll-mediated antifungal defense in serpin-deficient Drosophila. Science 1999; 285:1917–1919.

    PubMed  CAS  Google Scholar 

  107. Lemaitre B, Nicolas E, Michaut L et al. The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 1996; 86:973–983.

    PubMed  CAS  Google Scholar 

  108. Michel T, Reichhart JM, Hoffmann JA et al. Drosophila Toll is activated by Gram-positive bacteria through a circulating peptidoglycan recognition protein. Nature 2001; 414:756–759.

    PubMed  CAS  Google Scholar 

  109. Akira S, Takeda K, Kaisho T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol 2001; 2:675–680.

    PubMed  CAS  Google Scholar 

  110. Gottar M, Gobert V, Michel T et al. The Drosophila immune response against Gram-negative bacteria is mediated by a peptidoglycan recognition protein. Nature 2002; 416:640–644.

    PubMed  CAS  Google Scholar 

  111. Ramet M, Manfruelli P, Pearson A et al. Functional genomic analysis of phagocytosis and identification of a Drosophila receptor for E. coli. Nature 2002; 416:644–648.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  114. Grosshans J, Bergmann A, Haffter P et al. Activation of the kinase Pelle by Tube in the dorsoventral signal transduction pathway of Drosophila embryo. Nature 1994; 372:563–566.

    PubMed  CAS  Google Scholar 

  115. Galindo RL, Edwards DN, Gillespie SK et al. Interaction of the Pelle kinase with the membrane-associated protein tube is required for transduction of the dorsoventral signal in Drosophila embryos. Development 1995; 121:2209–2218.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  119. Bergmann A, Stein D, Geisler R et al. A gradient of cytoplasmic Cactus degradation establishes the nuclear localization gradient of the dorsal morphogen in Drosophila. Mech Dev 1996; 60:109–123.

    PubMed  CAS  Google Scholar 

  120. Shen B, Liu H, Skolnik EY et al. Physical and functional interactions between Drosophila TRAF2 and Pelle kinase contribute to Dorsal activation. Proc Natl Acad Sci USA 2001; 98:8596–8601.

    PubMed  CAS  Google Scholar 

  121. Zapata JM, Matsuzawa S, Godzik A et al. The Drosophila tumor necrosis factor receptor-associated factor-1 (DTRAF1) interacts with Pelle and regulates NF-kappaB activity. J Biol Chem 2000; 275:12102–12107.

    PubMed  CAS  Google Scholar 

  122. Liu H, Su YC, Becker E et al. A Drosophila TNF-receptor-associated factor (TRAF) binds the ste20 kinase Misshapen and activates Jun kinase. Curr Biol 1999; 9:101–104.

    PubMed  CAS  Google Scholar 

  123. Bacher S, Grosshans J, Droge W et al. The Drosophila proteins Pelle and Tube induce JNK/AP-1 activity in mammalian cells. FEBS Lett 2001; 497:153–158.

    PubMed  CAS  Google Scholar 

  124. Muzio M, Natoli G, Saccani S et al. The human Toll signaling pathway: Dvergence of nuclear factor kappaB and JNK/SAPK activation upstream of tumor necrosis factor receptor-associated factor 6 (TRAF6). J Exp Med 1998; 187:2097–2101.

    PubMed  CAS  Google Scholar 

  125. Rutschmann S, Jung AC, Hetru C et al. The Rel protein DIF mediates the antifungal but not the antibacterial host defense in Drosophila. Immunity 2000; 12:569–580.

    PubMed  CAS  Google Scholar 

  126. Manfruelli P, Reichhart JM, Steward R et al. A mosaic analysis in Drosophila fat body cells of the control of antimicrobial peptide genes by the Rel proteins Dorsal and DIF. EMBO J 1999; 18:3380–3391.

    PubMed  CAS  Google Scholar 

  127. Stein D, Goltz JS, Jurcsak J et al. The Dorsal-related immunity factor (Dif) can define the dorsal-ventral axis of polarity in the Drosophila embryo. Development 1998; 125:2159–2169.

    PubMed  CAS  Google Scholar 

  128. Ip YT, Reach M, Engstrom Y et al. Dif, a dorsal-related gene that mediates an immune response in Drosophila. Cell 1993; 75:753–763.

    PubMed  CAS  Google Scholar 

  129. Wu LP, Anderson KV. Regulated nuclear import of Rel proteins in the Drosophila immune response. Nature 1998; 392:93–97.

    PubMed  CAS  Google Scholar 

  130. Avila A, Silverman N, Diaz-Meco MT et al. The Drosophila atypical protein kinase C-ref(2)p complex constitutes a conserved module for signaling in the Toll pathway. Mol Cell Biol 2002; 22:8787–8795.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  132. Sanz L, Diaz-Meco MT, Nakano H et al. The atypical PKC-interacting protein p62 channels NF-kappaB activation by the IL-1-TRAF6 pathway. EMBO J 2000; 19:1576–1586.

    PubMed  CAS  Google Scholar 

  133. Rutschmann S, Jung AC, Zhou R et al. Role of Drosophila IKK gamma in a Toll-independent antibacterial immune response. Nat Immunol 2000; 1:342–347.

    PubMed  CAS  Google Scholar 

  134. Silverman N, Zhou R, Stoven S et al. A Drosophila IkappaB kinase complex required for Relish cleavage and antibacterial immunity. Genes Dev 2000; 14:2461–2471.

    PubMed  CAS  Google Scholar 

  135. Kim YS, Han SJ, Ryu JH et al. Lipopolysaccharide-activated kinase, an essential component for the induction of the antimicrobial peptide genes in Drosophila melanogaster cells. J Biol Chem 2000; 275:2071–2079.

    PubMed  CAS  Google Scholar 

  136. Hedengren M, Asling B, Dushay MS et al. Relish, a central factor in the control of humoral but not cellular immunity in Drosophila. Mol Cell 1999; 4:827–837.

    PubMed  CAS  Google Scholar 

  137. Choe KM, Werner T, Stoven S et al. Requirement for a peptidoglycan recognition protein (PGRP) in Relish activation and antibacterial immune responses in Drosophila. Science 2002; 296:359–362.

    PubMed  CAS  Google Scholar 

  138. Dejardin E, Droin NM, Delhase M et al. The lymphotoxin-beta receptor induces different patterns of gene expression via two NF-kappaB pathways. Immunity 2002; 17:525–535.

    PubMed  CAS  Google Scholar 

  139. Claudio E, Brown K, Park S et al. BAFF-induced NEMO-independent processing of NF-kappa B2 in maturing B cells. Nat Immunol 2002; 3:958–965.

    PubMed  CAS  Google Scholar 

  140. Senftleben U, Cao Y, Xiao G et al. Activation by IKKalpha of a second, evolutionary conserved, NF-kappa B signaling pathway. Science 2001; 293:1495–1499.

    PubMed  CAS  Google Scholar 

  141. Vidal S, Khush RS, Leulier F et al. Mutations in the Drosophila dTAKl gene reveal a conserved function for MAPKKKs in the control of rel/NF-kappaB-dependent innate immune responses. Genes Dev 2001; 15:1900–1912.

    PubMed  CAS  Google Scholar 

  142. Aliprantis AO, Yang RB, Mark MR et al. Cell activation and apoptosis by bacterial lipoproteins through Toll-like receptor-2. Science 1999; 285:736–739.

    PubMed  CAS  Google Scholar 

  143. Aliprantis AO, Yang RB, Weiss DS et al. The apoptotic signaling pathway activated by Toll-like receptor-2. EMBO J 2000; 19:3325–3336.

    PubMed  CAS  Google Scholar 

  144. Schneider P, Tschopp J. Apoptosis induced by death receptors. Pharm Acta Helv 2000; 74:281–286.

    PubMed  CAS  Google Scholar 

  145. Hu S, Yang X. dFADD, a novel death domain-containing adapter protein for the Drosophila caspase DREDD. J Biol Chem 2000; 275:30761–30764.

    PubMed  CAS  Google Scholar 

  146. Chen P, Rodriguez A, Erskine R et al. Dredd, a novel effector of the apoptosis activators reaper, grim, and hid in Drosophila. Dev Biol 1998; 201:202–216.

    PubMed  CAS  Google Scholar 

  147. Rodriguez A, Oliver H, Zou H et al. Dark is a Drosophila homologue of Apaf-l/CED-4 and functions in an evolutionarily conserved death pathway. Nat Cell Biol 1999; 1:272–279.

    PubMed  CAS  Google Scholar 

  148. Mochida Y, Takeda K, Saitoh M et al. ASK1 inhibits interleukin-1-induced NF-kappaB activity through disruption of TRAF6-TAK1 interaction. J Biol Chem 2000; 275:32747–32752.

    PubMed  CAS  Google Scholar 

  149. Evans PC, Taylor ER, Coadwell J et al. Isolation and characterization of two novel A20-like proteins. Biochem J 2001; 357:617–623.

    PubMed  CAS  Google Scholar 

  150. Kopp E, Medzhitov R, Carothers J et al. ECSIT is an evolutionarily conserved intermediate in the Toll/IL-1 signal transduction pathway. Genes Dev 1999; 13:2059–2071.

    PubMed  CAS  Google Scholar 

  151. Wong BR, Besser D, Kim N et al. TRANCE, a TNF family member, activates Akt/PKB through a signaling complex involving TRAF6 and c-Src. Mol Cell 1999; 4:1041–1049.

    PubMed  CAS  Google Scholar 

  152. Vig E, Green M, Liu Y et al. SIMPL is a tumor necrosis factor-specific regulator of nuclear factor-kappaB activity. J Biol Chem 2001; 276:7859–7866.

    PubMed  CAS  Google Scholar 

  153. Ling L, Goeddel DV. T6BP, a TRAF6-interacting protein involved in IL-1 signaling. Proc Natl Acad Sci USA 2000; 97:9567–9572.

    PubMed  CAS  Google Scholar 

  154. Pype S, Declercq W, Ibrahimi A et al. TTRAP, a novel protein that associates with CD40, tumor necrosis factor (TNF) receptor-75 and TNF receptor-associated factors (TRAFs), and that inhibits nuclear factor-kappa B activation. J Biol Chem 2000; 275:18586–18593.

    PubMed  CAS  Google Scholar 

  155. Shin JN, Kim I, Lee JS et al. A novel zinc finger protein that inhibits osteoclastogenesis and the function of tumor necrosis factor receptor-associated factor 6. J Biol Chem 2002; 277:8346–8353.

    PubMed  CAS  Google Scholar 

  156. Takatsuna H, Kato H, Gohda J et al. Identification of TIFA as an adapter protein that links TRAF6 to IRAK-1 in IL-1 receptor signaling. J Biol Chem 2003; 278:12144–12150.

    PubMed  CAS  Google Scholar 

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  1. Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany

    Harald Wajant, Peter Scheurich & Frank Henkler

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  1. Harald Wajant
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Wajant, H., Scheurich, P., Henkler, F. (2005). Interleukin-1 Receptor/Toll-Like Receptor Signaling. In: Toll and Toll-Like Receptors: An Immunologic Perspective. Molecular Biology Intelligence Unit. Springer, Boston, MA. https://doi.org/10.1007/0-387-27445-6_5

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