tnf receptor associated factor 6


Summary: A signal transducing tumor necrosis factor receptor associated factor that is involved in regulation of NF-KAPPA B signalling and activation of JNK MITOGEN-ACTIVATED PROTEIN KINASES.

Top Publications

  1. King C, Kobayashi T, Cejas P, Kim T, Yoon K, Kim G, et al. TRAF6 is a T cell-intrinsic negative regulator required for the maintenance of immune homeostasis. Nat Med. 2006;12:1088-92 pubmed
    ..These data identify a previously unrecognized role for TRAF6 in the maintenance of peripheral tolerance, and suggest the presence of a T cell-intrinsic control mechanism to render responder T cells susceptible to tolerizing signals. ..
  2. Zirlik A, Bavendiek U, Libby P, MacFarlane L, Gerdes N, Jagielska J, et al. TRAF-1, -2, -3, -5, and -6 are induced in atherosclerotic plaques and differentially mediate proinflammatory functions of CD40L in endothelial cells. Arterioscler Thromb Vasc Biol. 2007;27:1101-7 pubmed
    ..These results implicate endothelial TRAF-1, -2, -3, -5, and -6 in CD40 signaling in atherogenesis, identifying these molecules as potential targets for selective therapeutic intervention. ..
  3. Fukushima T, Matsuzawa S, Kress C, Bruey J, Krajewska M, Lefebvre S, et al. Ubiquitin-conjugating enzyme Ubc13 is a critical component of TNF receptor-associated factor (TRAF)-mediated inflammatory responses. Proc Natl Acad Sci U S A. 2007;104:6371-6 pubmed
    ..These findings document a critical role for Ubc13 in inflammatory responses and suggest that agents reducing Ubc13 activity could have therapeutic utility. ..
  4. Takeda K, Akira S. TLR signaling pathways. Semin Immunol. 2004;16:3-9 pubmed
    ..Thus, TIR domain-containing adaptors provide specificity of TLR signaling. ..
  5. Uematsu S, Sato S, Yamamoto M, Hirotani T, Kato H, Takeshita F, et al. Interleukin-1 receptor-associated kinase-1 plays an essential role for Toll-like receptor (TLR)7- and TLR9-mediated interferon-{alpha} induction. J Exp Med. 2005;201:915-23 pubmed
    ..These results indicated that IRAK-1 is a specific regulator for TLR7- and TLR9-mediated IFN-alpha induction in pDCs. ..
  6. Takaoka A, Yanai H, Kondo S, Duncan G, Negishi H, Mizutani T, et al. Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors. Nature. 2005;434:243-9 pubmed
    ..Thus, our study identifies IRF-5 as a new, principal downstream regulator of the TLR-MyD88 signalling pathway and a potential target of therapeutic intervention to control harmful immune responses. ..
  7. Korchnak A, Zhan Y, Aguilar M, Chadee D. Cytokine-induced activation of mixed lineage kinase 3 requires TRAF2 and TRAF6. Cell Signal. 2009;21:1620-5 pubmed publisher
    ..These results reveal a novel mechanism for MLK3 activation by the pro-inflammatory cytokines TNF and IL-1 beta. ..
  8. Kobayashi T, Walsh P, Walsh M, Speirs K, Chiffoleau E, King C, et al. TRAF6 is a critical factor for dendritic cell maturation and development. Immunity. 2003;19:353-63 pubmed
    ..Together these results indicate that TRAF6 regulates the critical processes required for maturation, activation, and development of DCs, the primary cellular bridge between innate and adaptive immunity. ..
  9. Wu H, Arron J. TRAF6, a molecular bridge spanning adaptive immunity, innate immunity and osteoimmunology. Bioessays. 2003;25:1096-105 pubmed
    ..By virtue of its many signaling roles, TRAF6 represents an important target in the regulation of many disease processes, including immunity, inflammation and osteoporosis. ..

Scientific Experts

More Information


  1. Hostager B. Roles of TRAF6 in CD40 signaling. Immunol Res. 2007;39:105-14 pubmed
  2. Funakoshi Tago M, Tago K, Hayakawa M, Tominaga S, Ohshio T, Sonoda Y, et al. TRAF6 is a critical signal transducer in IL-33 signaling pathway. Cell Signal. 2008;20:1679-86 pubmed publisher
    ..Thus, these data demonstrate that TRAF6 plays a pivotal role in IL-33 signaling pathway through its ubiquitin ligase activity. ..
  3. Miyahara T, Koyama H, Miyata T, Shigematsu H, Inoue J, Takato T, et al. Inflammatory signaling pathway containing TRAF6 contributes to neointimal formation via diverse mechanisms. Cardiovasc Res. 2004;64:154-64 pubmed
    ..TRAF6 plays important roles in cell replication and migration, besides promotion of inflammatory cell infiltration and suppression of apoptosis. ..
  4. Kobayashi K, Hernandez L, Galan J, Janeway C, Medzhitov R, Flavell R. IRAK-M is a negative regulator of Toll-like receptor signaling. Cell. 2002;110:191-202 pubmed
    ..Endotoxin tolerance, a protection mechanism against endotoxin shock, was significantly reduced in IRAK-M(-/-) cells. Thus, IRAK-M regulates TLR signaling and innate immune homeostasis. ..
  5. Huang Q, Yang J, Lin Y, Walker C, Cheng J, Liu Z, et al. Differential regulation of interleukin 1 receptor and Toll-like receptor signaling by MEKK3. Nat Immunol. 2004;5:98-103 pubmed
    ..Note: In the version of this article originally published online, the third author's name was incorrect. The correct author name should be Yong Lin. This error has been corrected for the HTML and print versions of this article. ..
  6. Kawai T, Takeuchi O, Fujita T, Inoue J, Muhlradt P, Sato S, et al. Lipopolysaccharide stimulates the MyD88-independent pathway and results in activation of IFN-regulatory factor 3 and the expression of a subset of lipopolysaccharide-inducible genes. J Immunol. 2001;167:5887-94 pubmed
  7. Kaji K, Katogi R, Azuma Y, Naito A, Inoue J, Kudo A. Tumor necrosis factor alpha-induced osteoclastogenesis requires tumor necrosis factor receptor-associated factor 6. J Bone Miner Res. 2001;16:1593-9 pubmed
    ..Thus, we have provided the first evidence showing that TRAF6 is involved in TNF-alpha-induced osteoclastogenesis. ..
  8. Yang Y, Yin C, Pandey A, Abbott D, Sassetti C, Kelliher M. NOD2 pathway activation by MDP or Mycobacterium tuberculosis infection involves the stable polyubiquitination of Rip2. J Biol Chem. 2007;282:36223-9 pubmed
    ..tuberculosis-induced Rip2 polyubiquitination appears MyD88-independent. Collectively, these data reveal that the NOD2 pathway is ubiquitin-regulated and that Rip2 employs a ubiquitin-dependent mechanism to achieve NF-kappaB activation. ..
  9. Ye H, Arron J, Lamothe B, Cirilli M, Kobayashi T, Shevde N, et al. Distinct molecular mechanism for initiating TRAF6 signalling. Nature. 2002;418:443-7 pubmed
    ..Our studies identify a universal mechanism by which TRAF6 regulates several signalling cascades in adaptive immunity, innate immunity and bone homeostasis. ..
  10. Inoue J, Gohda J, Akiyama T. Characteristics and biological functions of TRAF6. Adv Exp Med Biol. 2007;597:72-9 pubmed
    ..The role of TRAF6 in osteoclastogenesis and the molecular mechanisms ofTRAF6-mediated signal transduction are described in other chapters. ..
  11. Takayanagi H, Kim S, Koga T, Nishina H, Isshiki M, Yoshida H, et al. Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev Cell. 2002;3:889-901 pubmed
    ..Thus, NFATc1 may represent a master switch for regulating terminal differentiation of osteoclasts, functioning downstream of RANKL. ..
  12. Walsh D, Greene C, Carroll T, Taggart C, Gallagher P, O Neill S, et al. Interleukin-8 up-regulation by neutrophil elastase is mediated by MyD88/IRAK/TRAF-6 in human bronchial epithelium. J Biol Chem. 2001;276:35494-9 pubmed
    ..These findings may have implications for therapeutic treatments in the cystic fibrosis condition. ..
  13. Rothenfusser S, Goutagny N, DiPerna G, Gong M, Monks B, Schoenemeyer A, et al. The RNA helicase Lgp2 inhibits TLR-independent sensing of viral replication by retinoic acid-inducible gene-I. J Immunol. 2005;175:5260-8 pubmed
    ..We propose that Lgp2 acts as a negative feedback regulator of antiviral signaling by sequestering dsRNA from RIG-I. ..
  14. Sato S, Sugiyama M, Yamamoto M, Watanabe Y, Kawai T, Takeda K, 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-li. J Immunol. 2003;171:4304-10 pubmed
    ..Taken together, these results demonstrate that TRIF associates with TRAF6 and TBK1 independently, and activates two distinct transcription factors, NF-kappaB and IFN regulatory factor-3, respectively. ..
  15. Ning S, Campos A, Darnay B, Bentz G, Pagano J. TRAF6 and the three C-terminal lysine sites on IRF7 are required for its ubiquitination-mediated activation by the tumor necrosis factor receptor family member latent membrane protein 1. Mol Cell Biol. 2008;28:6536-46 pubmed publisher
    ..This is the first evidence to imply that ubiquitination is required for phosphorylation and activation of a transcription factor. ..
  16. Armstrong A, Tometsko M, Glaccum M, Sutherland C, Cosman D, Dougall W. A RANK/TRAF6-dependent signal transduction pathway is essential for osteoclast cytoskeletal organization and resorptive function. J Biol Chem. 2002;277:44347-56 pubmed
    ..These studies are the first to define the functional domains of the RANK cytoplasmic tail that control specific differentiation and activation pathways in osteoclasts. ..
  17. Zhang Y, Heulsmann A, Tondravi M, Mukherjee A, Abu Amer Y. Tumor necrosis factor-alpha (TNF) stimulates RANKL-induced osteoclastogenesis via coupling of TNF type 1 receptor and RANK signaling pathways. J Biol Chem. 2001;276:563-8 pubmed
    ..Our data suggest that exuberant TNF-induced osteoclastogensis is the result of coupling between RANK and TNFr1 and is dependent upon signals transmitted by the latter receptor. ..
  18. Mochida Y, Takeda K, Saitoh M, Nishitoh H, Amagasa T, Ninomiya Tsuji J, et al. ASK1 inhibits interleukin-1-induced NF-kappa B activity through disruption of TRAF6-TAK1 interaction. J Biol Chem. 2000;275:32747-52 pubmed
    ..These results provide a new insight in the mode of action of MAPKKK family members; two distinct MAPKKKs in the same MAP kinase cascades directly interact and exert opposite effects in another signaling pathway, NF-kappaB. ..
  19. Schwandner R, Yamaguchi K, Cao Z. Requirement of tumor necrosis factor receptor-associated factor (TRAF)6 in interleukin 17 signal transduction. J Exp Med. 2000;191:1233-40 pubmed
    ..Together, these results indicate that TRAF6, but not TRAF2, is a crucial component in the IL-17 signaling pathway leading to proinflammatory responses. ..
  20. Windheim M, Stafford M, Peggie M, Cohen P. Interleukin-1 (IL-1) induces the Lys63-linked polyubiquitination of IL-1 receptor-associated kinase 1 to facilitate NEMO binding and the activation of IkappaBalpha kinase. Mol Cell Biol. 2008;28:1783-91 pubmed publisher
    ..Our data suggest a model in which the recruitment of the NEMO-IKK complex to K63-pUb-IRAK1 and the recruitment of the TAK1 complex to TRAF6 facilitate the TAK1-catalyzed activation of IKK by the TRAF6-IRAK1 complex. ..
  21. Conze D, Wu C, Thomas J, Landstrom A, Ashwell J. Lys63-linked polyubiquitination of IRAK-1 is required for interleukin-1 receptor- and toll-like receptor-mediated NF-kappaB activation. Mol Cell Biol. 2008;28:3538-47 pubmed publisher
    ..Thus, K63-linked polyubiquitination of proximal signaling proteins is a common mechanism used by diverse innate immune receptors for recruiting IKK and activating NF-kappaB. ..
  22. Takaesu G, Kishida S, Hiyama A, Yamaguchi K, Shibuya H, Irie K, 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;5:649-58 pubmed
    ..These results define TAB2 as an adaptor linking TAK1 and TRAF6 and as a mediator of TAK1 activation in the IL-1 signaling pathway. ..
  23. Abbott D, Yang Y, Hutti J, Madhavarapu S, Kelliher M, Cantley L. Coordinated regulation of Toll-like receptor and NOD2 signaling by K63-linked polyubiquitin chains. Mol Cell Biol. 2007;27:6012-25 pubmed
    ..These findings suggest a biochemical mechanism for the faulty cytokine balance seen in Crohn's disease. ..
  24. Sorrentino A, Thakur N, Grimsby S, Marcusson A, von Bulow V, Schuster N, et al. The type I TGF-beta receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner. Nat Cell Biol. 2008;10:1199-207 pubmed publisher
    ..Our data show that TGF-beta specifically activates TAK1 through interaction of TbetaRI with TRAF6, whereas activation of Smad2 is not dependent on TRAF6. ..
  25. Yoshida R, Takaesu G, Yoshida H, Okamoto F, Yoshioka T, Choi Y, et al. TRAF6 and MEKK1 play a pivotal role in the RIG-I-like helicase antiviral pathway. J Biol Chem. 2008;283:36211-20 pubmed publisher
    ..These data suggest that IPS-1 requires TRAF6 and MEKK1 to activate NF-kappaB and mitogen-activated protein kinases that are critical for the optimal induction of type I interferons. ..
  26. Hou J, Wang P, Lin L, Liu X, Ma F, An H, et al. MicroRNA-146a feedback inhibits RIG-I-dependent Type I IFN production in macrophages by targeting TRAF6, IRAK1, and IRAK2. J Immunol. 2009;183:2150-8 pubmed publisher
    ..Therefore, we demonstrate that miR-146a, up-regulated during viral infection, is a negative regulator of the RIG-I-dependent antiviral pathway by targeting TRAF6, IRAK1, and IRAK2. ..
  27. Bradley J, Pober J. Tumor necrosis factor receptor-associated factors (TRAFs). Oncogene. 2001;20:6482-91 pubmed
    ..TRAF proteins are expressed in normal and diseased tissue in a regulated fashion, suggesting that they play an important role in physiological and pathological processes. ..
  28. Ahonen C, Manning E, Erickson L, O CONNOR B, Lind E, Pullen S, et al. The CD40-TRAF6 axis controls affinity maturation and the generation of long-lived plasma cells. Nat Immunol. 2002;3:451-6 pubmed
    ..In addition, they define the roles that TRAF-dependent and TRAF-independent pathways play in regulating antigen-driven B cell differentiation. ..
  29. Jono H, Lim J, Chen L, Xu H, Trompouki E, Pan Z, et al. NF-kappaB is essential for induction of CYLD, the negative regulator of NF-kappaB: evidence for a novel inducible autoregulatory feedback pathway. J Biol Chem. 2004;279:36171-4 pubmed
    ..In addition, TRAF2 and TRAF6 appear to be differentially involved in NF-kappaB-dependent induction of CYLD by TNF-alpha and NTHi. These findings provide novel insights into the autoregulation of NF-kappaB activation. ..
  30. Lutgens E, Lievens D, Beckers L, Wijnands E, Soehnlein O, Zernecke A, et al. Deficient CD40-TRAF6 signaling in leukocytes prevents atherosclerosis by skewing the immune response toward an antiinflammatory profile. J Exp Med. 2010;207:391-404 pubmed publisher
  31. Pauley K, Satoh M, Chan A, Bubb M, Reeves W, Chan E. Upregulated miR-146a expression in peripheral blood mononuclear cells from rheumatoid arthritis patients. Arthritis Res Ther. 2008;10:R101 pubmed publisher
  32. Turer E, Tavares R, Mortier E, Hitotsumatsu O, Advincula R, Lee B, et al. Homeostatic MyD88-dependent signals cause lethal inflamMation in the absence of A20. J Exp Med. 2008;205:451-64 pubmed publisher
    ..These findings provide novel insights into how physiological TLR signals are regulated. ..
  33. Donners M, Beckers L, Lievens D, Munnix I, Heemskerk J, Janssen B, et al. The CD40-TRAF6 axis is the key regulator of the CD40/CD40L system in neointima formation and arterial remodeling. Blood. 2008;111:4596-604 pubmed publisher
    ..This identifies the CD40-TRAF6 axis as a potential therapeutic target in vascular disease. ..
  34. 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;173:2913-7 pubmed
    ..These results indicate that TRAF6 is essential for MyD88-dependent signaling but is not required for TIR domain-containing adaptor-inducing IFN-beta (TRIF)-dependent signaling. ..
  35. Kadono Y, Okada F, Perchonock C, Jang H, Lee S, Kim N, et al. Strength of TRAF6 signalling determines osteoclastogenesis. EMBO Rep. 2005;6:171-6 pubmed
    ..Our results suggest that differences in the osteoclastogenesis-inducing capacity of TRANCE-R versus other TRAF6-associated receptors may in part stem from a quantitative difference in the TRAF6-mediated signals. ..
  36. Taganov K, Boldin M, Chang K, Baltimore D. NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci U S A. 2006;103:12481-6 pubmed
  37. Maezawa Y, Nakajima H, Suzuki K, Tamachi T, Ikeda K, Inoue J, et al. Involvement of TNF receptor-associated factor 6 in IL-25 receptor signaling. J Immunol. 2006;176:1013-8 pubmed
    ..Taken together, these results indicate that TRAF6 plays a critical role in IL-25R-mediated NF-kappaB activation and gene expression. ..
  38. Mason N, Fiore J, Kobayashi T, Masek K, Choi Y, Hunter C. TRAF6-dependent mitogen-activated protein kinase activation differentially regulates the production of interleukin-12 by macrophages in response to Toxoplasma gondii. Infect Immun. 2004;72:5662-7 pubmed
    ..The studies presented here demonstrate for the first time that the production of IL-12(p40) in response to toxoplasma is dependent upon TRAF6 and p38 MAPK. ..
  39. Shim J, Xiao C, Paschal A, Bailey S, Rao P, Hayden M, et al. TAK1, but not TAB1 or TAB2, plays an essential role in multiple signaling pathways in vivo. Genes Dev. 2005;19:2668-81 pubmed
    ..Therefore, our studies suggests that TAK1 acts as an upstream activating kinase for IKKbeta and JNK, but not IKKalpha, revealing an unexpectedly specific role of TAK1 in inflammatory signaling pathways. ..
  40. Xu L, Wang Y, Han K, Li L, Zhai Z, Shu H. VISA is an adapter protein required for virus-triggered IFN-beta signaling. Mol Cell. 2005;19:727-40 pubmed
    ..These findings suggest that VISA is critically involved in both virus-triggered TLR3-independent and TLR3-mediated antiviral IFN signaling. ..
  41. Boone D, Turer E, Lee E, Ahmad R, Wheeler M, Tsui C, et al. The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses. Nat Immunol. 2004;5:1052-60 pubmed
    ..The critical function of this deubiquitinating enzyme in the restriction of TLR signals emphasizes the importance of the regulation of ubiquitin conjugation in innate immune cells. ..
  42. Deng L, Wang C, Spencer E, Yang L, Braun A, You J, et al. Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Cell. 2000;103:351-61 pubmed
    ..These results unveil a new regulatory function for ubiquitin, in which IKK is activated through the assembly of K63-linked polyubiquitin chains. ..
  43. Kobayashi N, Kadono Y, Naito A, Matsumoto K, Yamamoto T, Tanaka S, et al. Segregation of TRAF6-mediated signaling pathways clarifies its role in osteoclastogenesis. EMBO J. 2001;20:1271-80 pubmed
    ..Thus, TRAF6 plays essential roles in both the differentiation and maturation of osteoclasts by activating various kinases via its multiple domains. ..
  44. Sun L, Deng L, Ea C, Xia Z, Chen Z. The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation by BCL10 and MALT1 in T lymphocytes. Mol Cell. 2004;14:289-301 pubmed
    ..These results reveal an oligomerization --> ubiquitination --> phosphorylation cascade that culminates in NF-kappaB activation in T lymphocytes. ..
  45. Jensen L, Whitehead A. Ubiquitin activated tumor necrosis factor receptor associated factor-6 (TRAF6) is recycled via deubiquitination. FEBS Lett. 2003;553:190-4 pubmed
    ..This indicates a unique mechanism of regulation of TRAF6 activity. ..
  46. Yoshida H, Jono H, Kai H, Li J. The tumor suppressor cylindromatosis (CYLD) acts as a negative regulator for toll-like receptor 2 signaling via negative cross-talk with TRAF6 AND TRAF7. J Biol Chem. 2005;280:41111-21 pubmed
    ..These findings provide novel insights into autoregulation and negative regulation of TLR signaling. ..
  47. Han K, Su X, Xu L, Bin L, Zhang J, Shu H. Mechanisms of the TRIF-induced interferon-stimulated response element and NF-kappaB activation and apoptosis pathways. J Biol Chem. 2004;279:15652-61 pubmed
  48. Chen Z. Ubiquitin signalling in the NF-kappaB pathway. Nat Cell Biol. 2005;7:758-65 pubmed
    ..Recent studies have revealed several enzymes involved in the ubiquitination and deubiquitination of signalling proteins that mediate IKK activation through a degradation-independent mechanism. ..
  49. Yamashita M, Fatyol K, Jin C, Wang X, Liu Z, Zhang Y. TRAF6 mediates Smad-independent activation of JNK and p38 by TGF-beta. Mol Cell. 2008;31:918-24 pubmed publisher
    ..Our results indicate that TGF-beta activates JNK and p38 through a mechanism similar to that operating in the interleukin-1beta/Toll-like receptor pathway. ..
  50. Trompouki E, Hatzivassiliou E, Tsichritzis T, Farmer H, Ashworth A, Mosialos G. CYLD is a deubiquitinating enzyme that negatively regulates NF-kappaB activation by TNFR family members. Nature. 2003;424:793-6 pubmed
    ..These results indicate that CYLD is a negative regulator of the cytokine-mediated activation of NF-kappaB that is required for appropriate cellular homeostasis of skin appendages. ..
  51. Manna S, Ramesh G. Interleukin-8 induces nuclear transcription factor-kappaB through a TRAF6-dependent pathway. J Biol Chem. 2005;280:7010-21 pubmed
    ..This is the first report that IL-8 induces NF-kappaB in a distinct pathway, and activation of NF-kappaB and its dependent genes may be one of the pathways of IL-8-induced inflammation and angiogenesis. ..
  52. Petroski M, Zhou X, Dong G, Daniel Issakani S, Payan D, Huang J. Substrate modification with lysine 63-linked ubiquitin chains through the UBC13-UEV1A ubiquitin-conjugating enzyme. J Biol Chem. 2007;282:29936-45 pubmed
  53. Kawai T, Sato S, Ishii K, Coban C, Hemmi H, Yamamoto M, et al. Interferon-alpha induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6. Nat Immunol. 2004;5:1061-8 pubmed
    ..These results indicate that TLR-mediated IFN-alpha induction requires the formation of a complex consisting of MyD88, TRAF6 and IRF7 as well as TRAF6-dependent ubiquitination. ..