Characteristics and Biological Functions of TRAF6

  • Jun-ichiro Inoue
  • Jin Gohda
  • Taishin Akiyama
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 597)


TRAF6 is divergent from other members of the TRAF family. Therefore, TRAF6 was expected to play physiological roles distinct from those of other TRAFs. In this chapter, we focused on the physiological functions specific to TRAF6 but not other TRAFs in immune system, formation of skin appendices, and nervous system development by describing abnormal phenotypes observed in TRAF6-deficient mice. The role of TRAF6 in osteoclastogenesis and the molecular mechanisms of TRAF6-mediated signal transduction are described in other chapters.


Major Histocompatibility Complex Class NFKB Activation Hypohidrotic Ectodermal Dysplasia Thymic Stroma TNFR Superfamily 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Ishida T, Mizushima S, Azuma S et al. Identification of TRAF6, a novel tumor necrosis factor receptor-associated factor protein that mediates signaling from an amino-terminal domain of the CD40 cytoplasmic region. J Biol Chem 1996; 271(46):28745–28748.PubMedCrossRefGoogle Scholar
  2. 2.
    Cao Z, Xiong J, Takeuchi M et al. TRAF6 is a signal transducer for interleukin-1. Nature 1996; 383(6599):443–446.PubMedCrossRefGoogle Scholar
  3. 3.
    Inoue J, Ishida T, Tsukamoto N et al. Tumor necrosis factor receptor-associated factor (TRAF) family: Adapter proteins that mediate cytokine signaling. Exp Cell Res 2000; 254(1):14–24.PubMedCrossRefGoogle Scholar
  4. 4.
    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(8):1015–1024.PubMedGoogle Scholar
  5. 5.
    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(6):353–362.PubMedCrossRefGoogle Scholar
  6. 6.
    Fitzgerald KA, O’Neill LA. The role of the interleukin-1/Toll-like receptor superfamily in inflammation and host defence. Microbes Infect 2000; 2(8):933–943.PubMedCrossRefGoogle Scholar
  7. 7.
    O’Neil LA. Signal transduction pathways activated by the IL-1 receptor/toll-like receptor superfamily. Curr Top Microbiol Immunol 2002; 270:47–61.Google Scholar
  8. 8.
    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(8):5567–5572.PubMedCrossRefGoogle Scholar
  9. 9.
    Kobayashi N, Kadono Y, Naito A et al. Segregation of TRAF6-mediated signaling pathways clarifies its role in osteoclastogenesis. EMBO J 2001; 20(6):1271–1280.PubMedCrossRefGoogle Scholar
  10. 10.
    Kawai T, Akira S. Pathogen recognition with Toll-like receptors. Curr Opin Immunol 2005; 17(4):338–344.PubMedCrossRefGoogle Scholar
  11. 11.
    O’Neill LA. The role of MyD88-like adapters in Toll-like receptor signal transduction. Biochem Soc Trans 2003; 31(Pt 3):643–647.CrossRefGoogle Scholar
  12. 12.
    O’Neill LA, Fitzgerald KA, Bowie AG. The Toll-IL-1 receptor adaptor family grows to five members. Trends Immunol 2003; 24(6):286–290.CrossRefGoogle Scholar
  13. 13.
    Sato S, Sugiyama M, Yamamoto M et al. Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF) associates with TNF receptor-associated factor 6 and TANK-binding kinase 1, and activates two distinct transcription factors, NF-kappa B and IFN-regulatory factor-3, in the Toll-like receptor signaling. J Immunol 2003; 171(8):4304–4310.PubMedGoogle Scholar
  14. 14.
    Jiang Z, Mak TW, Sen G et al. Toll-like receptor 3-mediated activation of NF-{kappa}B and IRF3 diverges at Toll-IL-1 receptor domain-containing adapter inducing IFN-ta. Proc Natl Acad Sci USA 2004.Google Scholar
  15. 15.
    Gohda J, Matsumura T, Inoue J. Cutting edge: TNFR-associated factor (TRAF) 6 is essential for MyD88-dependent pathway but not toll/IL-1 receptor domain-containing adaptor-inducing IFN-beta (TRIF)-dependent pathway in TLR signaling. J Immunol 2004; 173(5):2913–2917.PubMedGoogle Scholar
  16. 16.
    Yamamoto M, Sato S, Hemmi H et al. Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science 2003; 301(5633):640–643.PubMedCrossRefGoogle Scholar
  17. 17.
    Yamamoto M, Sato S, Hemmi H et al. TRAM is specifically involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway. Nat Immunol 2003; 4(11):1144–1150.PubMedCrossRefGoogle Scholar
  18. 18.
    Covert MW, Leung TH, Gaston JE et al. Achieving stability of lipopolysaccharide-induced NF-kappaB activation. Science 2005; 309(5742):1854–1857.PubMedCrossRefGoogle Scholar
  19. 19.
    Takaoka A, Yanai H, Kondo S et al. Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors. Nature 2005; 434(7030):243–249.PubMedCrossRefGoogle Scholar
  20. 20.
    Kawai T, Sato S, Ishii KJ et al. Interferon-alpha induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6. Nat Immunol 2004; 5(10):1061–1068.PubMedCrossRefGoogle Scholar
  21. 21.
    Honda K, Yanai H, Mizutani T et al. Role of a transductional-transcriptional processor complex involving MyD88 and IRF-7 in Toll-like receptor signaling. Proc Natl Acad Sci USA 2004; 101(43):15416–15421.PubMedCrossRefGoogle Scholar
  22. 22.
    Banchereau J, Briere F, Caux C et al. Immunobiology of dendritic cells. Annu Rev Immunol 2000; 18:767–811.PubMedCrossRefGoogle Scholar
  23. 23.
    Kobayashi T, Walsh PT, Walsh MC et al. TRAF6 is a critical factor for dendritic cell maturation and development. Immunity 2003; 19(3):353–363.PubMedCrossRefGoogle Scholar
  24. 24.
    De Togni P, Goellner J, Ruddle NH et al. Abnormal development of peripheral lymphoid organs in mice deficient in lymphotoxin. Science 1994; 264(5159):703–707.PubMedCrossRefGoogle Scholar
  25. 25.
    Koni PA, Sacca R, Lawton P et al. Distinct roles in lymphoid organogenesis for lymphotoxins alpha and beta revealed in lymphotoxin beta-deficient mice. Immunity 1997; 6(4):491–500.PubMedCrossRefGoogle Scholar
  26. 26.
    Dougall WC, Glaccum M, Charrier K et al. RANK is essential for osteoclast and lymph node development. Genes Dev 1999; 13(18):2412–2424.PubMedCrossRefGoogle Scholar
  27. 27.
    Yoshida H, Naito A, Inoue J et al. Different cytokines induce surface lymphotoxin-alphabeta on IL-7 receptor-alpha cells that differentially engender lymph nodes and Peyer’s patches. Immunity 2002; 17(6):823–833.PubMedCrossRefGoogle Scholar
  28. 28.
    Anderson G, Moore NC, Owen JJ et al. Cellular interactions in thymocyte development. Annu Rev Immunol 1996; 14:73–99.PubMedCrossRefGoogle Scholar
  29. 29.
    Akiyama T, Maeda S, Yamane S et al. Dependence of self-tolerance on TRAF6-directed development of thymic stroma. Science 2005; 308:248–251.PubMedCrossRefGoogle Scholar
  30. 30.
    Anderson MS, Venanzi ES, Klein L et al. Projection of an immunological self shadow within the thymus by the aire protein. Science 2002; 298(5597):1395–1401.PubMedCrossRefGoogle Scholar
  31. 31.
    Liston A, Lesage S, Wilson J et al. Aire regulates negative selection of organ-specific T cells. Nat Immunol 2003; 4(4):350–354.PubMedCrossRefGoogle Scholar
  32. 32.
    Burkly L, Hession C, Ogata L et al. Expression of relB is required for the development of thymic medulla and dendritic cells. Nature 1995; 373(6514):531–536.PubMedCrossRefGoogle Scholar
  33. 33.
    Weih F, Carrasco D, Durham SK et al. Multiorgan inflammation and hematopoietic abnormalities in mice with a targeted disruption of RelB, a member of the NF-kappa B/Rel family. Cell 1995; 80(2):331–340.PubMedCrossRefGoogle Scholar
  34. 34.
    Kajiura F, Sun S, Nomura T et al. NF-kappa B-inducing kinase establishes self-tolerance in a thymic stroma-dependent manner. J Immunol 2004; 172(4):2067–2075.PubMedGoogle Scholar
  35. 35.
    Xiao G, Harhaj EW, Sun SC. NF-kappaB-inducing kinase regulates the processing of NF-kappaB2 p100. Mol Cell 2001; 7(2):401–409.PubMedCrossRefGoogle Scholar
  36. 36.
    Naito A, Yoshida H, Nishioka E et al. TRAF6-deficient mice display hypohidrotic ectodermal dysplasia. Proc Natl Acad Sci USA 2002; 99(13):8766–8771.PubMedGoogle Scholar
  37. 37.
    Courtney JM, Blackburn J, Sharpe PT. The Ectodysplasin and NFkappaB signalling pathways in odontogenesis. Arch Oral Biol 2005; 50(2):159–163.PubMedCrossRefGoogle Scholar
  38. 38.
    Yan M, Wang LC, Hymowitz SG et al. Two-amino acid molecular switch in an epithelial morphogen that regulates binding to two distinct receptors. Science 2000; 290(5491):523–527.PubMedCrossRefGoogle Scholar
  39. 39.
    Kojima T, Morikawa Y, Copeland NG et al. TROY, a newly identified member of the tumor necrosis factor receptor superfamily, exhibits a homology with Edar and is expressed in embryonic skin and hair follicles. J Biol Chem 2000; 275(27):20742–20747.PubMedCrossRefGoogle Scholar
  40. 40.
    Ohazama A, Courtney JM, Tucker AS et al. Traf6 is essential for murine tooth cusp morphogenesis. Dev Dyn 2004; 229(1):131–135.PubMedCrossRefGoogle Scholar
  41. 41.
    Morlon A, Munnich A, Smahi A. TAB2, TRAF6 and TAK1 are involved in NF-{kappa}B activation induced by the TNF-receptor, Edar and its adaptator Edaradd. Hum Mol Genet 2005; 14(23):3751–3757.PubMedCrossRefGoogle Scholar
  42. 42.
    Shao Z, Browning JL, Lee X et al. TAJ/TROY, an orphan TNF receptor family member, binds Nogo-66 receptor 1 and regulates axonal regeneration. Neuron 2005; 45(3):353–359.PubMedCrossRefGoogle Scholar
  43. 43.
    Newton K, French DM, Yan M et al. Myodegeneration in EDA-A2 transgenic mice is prevented by XEDAR deficiency. Mol Cell Biol 2004; 24(4):1608–1613.PubMedCrossRefGoogle Scholar
  44. 44.
    Roux PP, Barker PA. Neurotrophin signaling through the p75 neurotrophin receptor. Prog Neurobiol 2002; 67(3):203–233.PubMedCrossRefGoogle Scholar
  45. 45.
    Khursigara G, Orlinick JR, Chao MV. Association of the p75 neurotrophin receptor with TRAF6. J Biol Chem 1999; 274(5):2597–2600.PubMedCrossRefGoogle Scholar
  46. 46.
    Yeiser EC, Rutkoski NJ, Naito A et al. Neurotrophin signaling through the p75 receptor is deficient in traf6−/− mice. J Neurosci 2004; 24(46):10521–10529.PubMedCrossRefGoogle Scholar
  47. 47.
    Geetha T, Kenchappa RS, Wooten MW et al. TRAF6-mediated ubiquitination regulates nuclear translocation of NRIF, the p75 receptor interactor. EMBO J 2005; 24(22):3859–3868.PubMedCrossRefGoogle Scholar
  48. 48.
    Geetha T, Jiang J, Wooten MW. Lysine 63 polyubiquitination of the nerve growth factor receptor TrkA directs internalization and signaling. Mol Cell 2005; 20(2):301–312.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2007

Authors and Affiliations

  • Jun-ichiro Inoue
    • 1
  • Jin Gohda
  • Taishin Akiyama
  1. 1.Division of Cellular and Molecular Biology, Department of Cancer Biology, Institute of Medical ScienceUniversity of TokyoTokyoJapan

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