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Gene Review

TRAF6  -  TNF receptor-associated factor 6, E3...

Homo sapiens

Synonyms: E3 ubiquitin-protein ligase TRAF6, Interleukin-1 signal transducer, MGC:3310, RING finger protein 85, RNF85, ...
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Disease relevance of TRAF6


High impact information on TRAF6

  • We find that TRAF6, a RING domain protein, functions together with Ubc13/Uev1A to catalyze the synthesis of unique polyubiquitin chains linked through lysine-63 (K63) of ubiquitin [7].
  • When it binds to its cell-surface receptor, IL-1 initiates a signalling cascade that leads to activation of the transcription factor NF-kappaB and is relayed through the protein TRAF6 and a succession of kinase enzymes, including NF-kappaB-inducing kinase (NIK) and I kappaB kinases (IKKs) [8].
  • Here we report the identification of a new TRAF family member, designated TRAF6 [9].
  • Mutation of K485 to R blocked TRAF6 and NGF-dependent polyubiquitination of TrkA, resulting in retention of the receptor on the membrane and an absence in activation of specific signaling pathways [10].
  • TAK1 is in turn activated by TRAF6, a RING domain ubiquitin ligase that facilitates the synthesis of lysine 63-linked polyubiquitin chains [11].

Chemical compound and disease context of TRAF6


Biological context of TRAF6


Anatomical context of TRAF6

  • Likewise, introduction of a dominant-negative TRAF6 into a wild-type (CD40(+)) macrophage cell line resulted in abrogation of CD40-mediated induction of inflammatory cytokine synthesis [18].
  • Thus, we examined the role of TRAF6 in CD40-mediated B lymphocyte effector functions using two approaches [16].
  • Finally, treatment of monocytes with a cell-permeable peptide corresponding to the TRAF6-binding motif of CD40 inhibited CD40 activation of ERK1/2, IKK, and inflammatory cytokine production [18].
  • Moreover, using vectors expressing dominant-negative forms of MyD88 and TRAF6, we established that LPS-induced activation of respiratory epithelial cells is largely dependent on TLR4 signaling intermediates [19].
  • We analyzed macrophages from TRAF6-deficient mice and made the following observations [20].

Associations of TRAF6 with chemical compounds

  • Tumor necrosis factor receptor-activated factor 6 (TRAF6) and the nuclear factor kappaB (NF-kappaB)-inducing kinase (NIK) are both involved in subsequent steps of NF-kappaB activation [21].
  • Conversely, a dominant negative version of TRAF6 failed to block hToll-induced activation of stress-activated protein kinase/c-Jun NH2-terminal kinases, thus suggesting an early divergence of the two pathways [21].
  • Lipopolysaccharide initiates a TRAF6-mediated endothelial survival signal [22].
  • TRAF6, in turn, enhances the kinase activity of c-Src leading to tyrosine phosphorylation of downstream signaling molecules such as c-Cbl [23].
  • Here, we demonstrate that TRANCE activates the antiapoptotic serine/threonine kinase Akt/PKB through a signaling complex involving c-Src and TRAF6 [23].
  • We examined the role of the ZF domains in interleukin-1, lipopolysaccharide, and RANKL signaling by reconstitution of TRAF6-deficient cells with point mutations or deletions of these ZF motifs [24].

Physical interactions of TRAF6

  • However, single aa substitution of Glu-235 in cyt-N of human CD40 with Ala abolishes the binding of TRAF6 to cyt-N and NFkappaB activation by cyt-N [25].
  • We also inducibly expressed in B cells a transfected "dominant-negative" TRAF6 molecule which contains only the C-terminal TRAF-binding domain of TRAF6 [16].
  • IL-8-induced NF-kappaB activation is not observed in a cell-permeable peptide that has TRAF6 binding motif-treated cells or IRAK-deficient cells [26].
  • Co-immunoprecipitation studies indicated that TRAF6 was able to interact with both Cezanne and TRABID [27].
  • Moreover, A20 was shown to directly interact with TRAF6 [28].
  • We found that Mal and TRAF6 directly interact in response to TLR2 and TLR4 stimulation, although membrane localization is not necessary to facilitate interaction [29].

Regulatory relationships of TRAF6

  • Furthermore, NFkappaB activation by cyt-C is inhibited by a kinase-negative form of NFkappaB-inducing kinase more efficiently than that by cyt-N, consistent with the result that NFkappaB activation by TRAF2 and TRAF5 is inhibited by a kinase-negative form of NFkappaB-inducing kinase more efficiently than that by TRAF6 [25].
  • Interleukin-8 induces nuclear transcription factor-kappaB through a TRAF6-dependent pathway [26].
  • In contrast, a higher degree of CD40 multimerization was necessary for maximal signaling in a cell line expressing a mutated CD40 (T254A) that signaled only through TRAF6 [30].
  • TIFA activates IkappaB kinase (IKK) by promoting oligomerization and ubiquitination of TRAF6 [31].
  • These results identify a specific role for Mal in TLR-mediated signaling in regulating NF-kappaB-dependent gene transcription via its interaction with TRAF6 [32].

Other interactions of TRAF6

  • These results suggest that CD40 activates ERK by both a Ras-dependent pathway and a Ras-independent pathway in which TRAF6 could be involved [33].
  • Furthermore, whereas poly(I.C)-induced NF-kappaB activation is completely abolished inTRAF6-/- MEFs, the signal-induced activation of IRF3 is TRAF6 independent [34].
  • Active RasVHa associated with IRAK, IRAK2, and TRAF6, but not MyD88 [35].
  • The site also binds TRAF2 and TRAF5, but not TRAF6 [36].
  • Second, a truncated version of A52R, which interacted with IRAK2 and not TRAF6, was unable to activate p38 [37].

Analytical, diagnostic and therapeutic context of TRAF6


  1. IL-1 induced chemokine production through the association of Syk with TNF receptor-associated factor-6 in nasal fibroblast lines. Yamada, T., Fujieda, S., Yanagi, S., Yamamura, H., Inatome, R., Yamamoto, H., Igawa, H., Saito, H. J. Immunol. (2001) [Pubmed]
  2. H. pylori activates NF-kappaB through a signaling pathway involving IkappaB kinases, NF-kappaB-inducing kinase, TRAF2, and TRAF6 in gastric cancer cells. Maeda, S., Yoshida, H., Ogura, K., Mitsuno, Y., Hirata, Y., Yamaji, Y., Akanuma, M., Shiratori, Y., Omata, M. Gastroenterology (2000) [Pubmed]
  3. TRAF6-deficient mice display hypohidrotic ectodermal dysplasia. Naito, A., Yoshida, H., Nishioka, E., Satoh, M., Azuma, S., Yamamoto, T., Nishikawa, S., Inoue, J. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  4. Activation of TRAF5 and TRAF6 signal cascades negatively regulates the latent replication origin of Epstein-Barr virus through p38 mitogen-activated protein kinase. Shirakata, M., Imadome, K.I., Okazaki, K., Hirai, K. J. Virol. (2001) [Pubmed]
  5. MyD88 and TNF receptor-associated factor 6 are critical signal transducers in Helicobacter pylori-infected human epithelial cells. Hirata, Y., Ohmae, T., Shibata, W., Maeda, S., Ogura, K., Yoshida, H., Kawabe, T., Omata, M. J. Immunol. (2006) [Pubmed]
  6. TRAF6 and MEKK1 play a pivotal role in the RIG-I-like helicase antiviral pathway. Yoshida, R., Takaesu, G., Yoshida, H., Okamoto, F., Yoshioka, T., Choi, Y., Akira, S., Kawai, T., Yoshimura, A., Kobayashi, T. J. Biol. Chem. (2008) [Pubmed]
  7. Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Deng, L., Wang, C., Spencer, E., Yang, L., Braun, A., You, J., Slaughter, C., Pickart, C., Chen, Z.J. Cell (2000) [Pubmed]
  8. The kinase TAK1 can activate the NIK-I kappaB as well as the MAP kinase cascade in the IL-1 signalling pathway. Ninomiya-Tsuji, J., Kishimoto, K., Hiyama, A., Inoue, J., Cao, Z., Matsumoto, K. Nature (1999) [Pubmed]
  9. TRAF6 is a signal transducer for interleukin-1. Cao, Z., Xiong, J., Takeuchi, M., Kurama, T., Goeddel, D.V. Nature (1996) [Pubmed]
  10. Lysine 63 polyubiquitination of the nerve growth factor receptor TrkA directs internalization and signaling. Geetha, T., Jiang, J., Wooten, M.W. Mol. Cell (2005) [Pubmed]
  11. TAB2 and TAB3 activate the NF-kappaB pathway through binding to polyubiquitin chains. Kanayama, A., Seth, R.B., Sun, L., Ea, C.K., Hong, M., Shaito, A., Chiu, Y.H., Deng, L., Chen, Z.J. Mol. Cell (2004) [Pubmed]
  12. Hsp70 inhibits lipopolysaccharide-induced NF-kappaB activation by interacting with TRAF6 and inhibiting its ubiquitination. Chen, H., Wu, Y., Zhang, Y., Jin, L., Luo, L., Xue, B., Lu, C., Zhang, X., Yin, Z. FEBS Lett. (2006) [Pubmed]
  13. TRAF6 is required for TRAF2-dependent CD40 signal transduction in nonhemopoietic cells. Davies, C.C., Mak, T.W., Young, L.S., Eliopoulos, A.G. Mol. Cell. Biol. (2005) [Pubmed]
  14. TRAF family proteins interact with the common neurotrophin receptor and modulate apoptosis induction. Ye, X., Mehlen, P., Rabizadeh, S., VanArsdale, T., Zhang, H., Shin, H., Wang, J.J., Leo, E., Zapata, J., Hauser, C.A., Reed, J.C., Bredesen, D.E. J. Biol. Chem. (1999) [Pubmed]
  15. CD40 signaling through tumor necrosis factor receptor-associated factors (TRAFs). Binding site specificity and activation of downstream pathways by distinct TRAFs. Pullen, S.S., Dang, T.T., Crute, J.J., Kehry, M.R. J. Biol. Chem. (1999) [Pubmed]
  16. Characterization of the roles of TNF receptor-associated factor 6 in CD40-mediated B lymphocyte effector functions. Jalukar, S.V., Hostager, B.S., Bishop, G.A. J. Immunol. (2000) [Pubmed]
  17. Toll-like receptor-4 mediates cigarette smoke-induced cytokine production by human macrophages. Karimi, K., Sarir, H., Mortaz, E., Smit, J.J., Hosseini, H., De Kimpe, S.J., Nijkamp, F.P., Folkerts, G. Respir. Res. (2006) [Pubmed]
  18. TNF receptor-associated factor 6 is an essential mediator of CD40-activated proinflammatory pathways in monocytes and macrophages. Mukundan, L., Bishop, G.A., Head, K.Z., Zhang, L., Wahl, L.M., Suttles, J. J. Immunol. (2005) [Pubmed]
  19. Response of human pulmonary epithelial cells to lipopolysaccharide involves Toll-like receptor 4 (TLR4)-dependent signaling pathways: evidence for an intracellular compartmentalization of TLR4. Guillot, L., Medjane, S., Le-Barillec, K., Balloy, V., Danel, C., Chignard, M., Si-Tahar, M. J. Biol. Chem. (2004) [Pubmed]
  20. 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. Gohda, J., Matsumura, T., Inoue, J. J. Immunol. (2004) [Pubmed]
  21. The human toll signaling pathway: divergence of nuclear factor kappaB and JNK/SAPK activation upstream of tumor necrosis factor receptor-associated factor 6 (TRAF6). Muzio, M., Natoli, G., Saccani, S., Levrero, M., Mantovani, A. J. Exp. Med. (1998) [Pubmed]
  22. Lipopolysaccharide initiates a TRAF6-mediated endothelial survival signal. Wong, F., Hull, C., Zhande, R., Law, J., Karsan, A. Blood (2004) [Pubmed]
  23. TRANCE, a TNF family member, activates Akt/PKB through a signaling complex involving TRAF6 and c-Src. Wong, B.R., Besser, D., Kim, N., Arron, J.R., Vologodskaia, M., Hanafusa, H., Choi, Y. Mol. Cell (1999) [Pubmed]
  24. The RING domain and first zinc finger of TRAF6 coordinate signaling by interleukin-1, lipopolysaccharide, and RANKL. Lamothe, B., Campos, A.D., Webster, W.K., Gopinathan, A., Hur, L., Darnay, B.G. J. Biol. Chem. (2008) [Pubmed]
  25. Two differently regulated nuclear factor kappaB activation pathways triggered by the cytoplasmic tail of CD40. Tsukamoto, N., Kobayashi, N., Azuma, S., Yamamoto, T., Inoue, J. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  26. Interleukin-8 induces nuclear transcription factor-kappaB through a TRAF6-dependent pathway. Manna, S.K., Ramesh, G.T. J. Biol. Chem. (2005) [Pubmed]
  27. Isolation and characterization of two novel A20-like proteins. Evans, P.C., Taylor, E.R., Coadwell, J., Heyninck, K., Beyaert, R., Kilshaw, P.J. Biochem. J. (2001) [Pubmed]
  28. The cytokine-inducible zinc finger protein A20 inhibits IL-1-induced NF-kappaB activation at the level of TRAF6. Heyninck, K., Beyaert, R. FEBS Lett. (1999) [Pubmed]
  29. MyD88 adapter-like (Mal)/TIRAP interaction with TRAF6 is critical for TLR2- and TLR4-mediated NF-kappaB proinflammatory responses. Verstak, B., Nagpal, K., Bottomley, S.P., Golenbock, D.T., Hertzog, P.J., Mansell, A. J. Biol. Chem. (2009) [Pubmed]
  30. High-affinity interactions of tumor necrosis factor receptor-associated factors (TRAFs) and CD40 require TRAF trimerization and CD40 multimerization. Pullen, S.S., Labadia, M.E., Ingraham, R.H., McWhirter, S.M., Everdeen, D.S., Alber, T., Crute, J.J., Kehry, M.R. Biochemistry (1999) [Pubmed]
  31. TIFA activates IkappaB kinase (IKK) by promoting oligomerization and ubiquitination of TRAF6. Ea, C.K., Sun, L., Inoue, J., Chen, Z.J. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  32. Mal interacts with tumor necrosis factor receptor-associated factor (TRAF)-6 to mediate NF-kappaB activation by toll-like receptor (TLR)-2 and TLR4. Mansell, A., Brint, E., Gould, J.A., O'Neill, L.A., Hertzog, P.J. J. Biol. Chem. (2004) [Pubmed]
  33. Tumor necrosis factor receptor-associated factor 6 (TRAF6) stimulates extracellular signal-regulated kinase (ERK) activity in CD40 signaling along a ras-independent pathway. Kashiwada, M., Shirakata, Y., Inoue, J.I., Nakano, H., Okazaki, K., Okumura, K., Yamamoto, T., Nagaoka, H., Takemori, T. J. Exp. Med. (1998) [Pubmed]
  34. Toll-like receptor 3-mediated activation of NF-kappaB and IRF3 diverges at Toll-IL-1 receptor domain-containing adapter inducing IFN-beta. Jiang, Z., Mak, T.W., Sen, G., Li, X. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  35. Ras participates in the activation of p38 MAPK by interleukin-1 by associating with IRAK, IRAK2, TRAF6, and TAK-1. McDermott, E.P., O'Neill, L.A. J. Biol. Chem. (2002) [Pubmed]
  36. Localization of the major NF-kappaB-activating site and the sole TRAF3 binding site of LMP-1 defines two distinct signaling motifs. Brodeur, S.R., Cheng, G., Baltimore, D., Thorley-Lawson, D.A. J. Biol. Chem. (1997) [Pubmed]
  37. Vaccinia virus protein A52R activates p38 mitogen-activated protein kinase and potentiates lipopolysaccharide-induced interleukin-10. Maloney, G., Schröder, M., Bowie, A.G. J. Biol. Chem. (2005) [Pubmed]
  38. ZNF216 Is an A20-like and IkappaB kinase gamma-interacting inhibitor of NFkappaB activation. Huang, J., Teng, L., Li, L., Liu, T., Li, L., Chen, D., Xu, L.G., Zhai, Z., Shu, H.B. J. Biol. Chem. (2004) [Pubmed]
  39. TRAF6, a molecular bridge spanning adaptive immunity, innate immunity and osteoimmunology. Wu, H., Arron, J.R. Bioessays (2003) [Pubmed]
  40. Association of the p75 neurotrophin receptor with TRAF6. Khursigara, G., Orlinick, J.R., Chao, M.V. J. Biol. Chem. (1999) [Pubmed]
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