TRAF6

TNF receptor-associated factor 6, E3 ubiquitin protein ligase
PDB rendering based on 1lb4.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1LB4​, 1LB5​, 1LB6​, 2ECI​, 2JMD​, 3HCS​, 3HCT​, 3HCU​
Identifiers
Symbols	TRAF6 ; MGC:3310; RNF85
External IDs	OMIM: 602355 MGI: 108072 HomoloGene: 3395 GeneCards: TRAF6 Gene
Gene ontology Molecular function • ubiquitin-protein transferase activity • tumor necrosis factor receptor binding • protein binding • zinc ion binding • ligase activity • protein kinase binding • mitogen-activated protein kinase kinase kinase binding • ubiquitin conjugating enzyme binding • ubiquitin protein ligase binding • thioesterase binding • identical protein binding • histone deacetylase binding • protein kinase B binding • protein N-terminus binding • ubiquitin protein ligase activity Cellular component • nucleus • nucleolus • cytoplasm • mitochondrion • lipid particle • cytosol • plasma membrane • cell cortex • cytoplasmic side of plasma membrane • endosome membrane • CD40 receptor complex • protein complex • perinuclear region of cytoplasm Biological process • negative regulation of transcription from RNA polymerase II promoter • activation of MAPK activity • protein polyubiquitination • ossification • neural tube closure • stimulatory C-type lectin receptor signaling pathway • toll-like receptor signaling pathway • positive regulation of T cell cytokine production • MyD88-dependent toll-like receptor signaling pathway • MyD88-independent toll-like receptor signaling pathway • protein complex assembly • I-kappaB kinase/NF-kappaB signaling • activation of NF-kappaB-inducing kinase activity • JNK cascade • antigen processing and presentation of exogenous peptide antigen via MHC class II • osteoclast differentiation • membrane protein intracellular domain proteolysis • positive regulation of protein ubiquitination • positive regulation of lipopolysaccharide-mediated signaling pathway • activation of protein kinase activity • positive regulation of interleukin-2 production • toll-like receptor 2 signaling pathway • toll-like receptor 3 signaling pathway • toll-like receptor 4 signaling pathway • toll-like receptor 5 signaling pathway • toll-like receptor 9 signaling pathway • toll-like receptor 10 signaling pathway • TRIF-dependent toll-like receptor signaling pathway • nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway • Fc-epsilon receptor signaling pathway • toll-like receptor TLR1:TLR2 signaling pathway • toll-like receptor TLR6:TLR2 signaling pathway • T-helper 1 type immune response • positive regulation of T cell proliferation • odontogenesis of dentin-containing tooth • myeloid dendritic cell differentiation • positive regulation of apoptotic process • negative regulation of apoptotic process • positive regulation of I-kappaB kinase/NF-kappaB signaling • positive regulation of JUN kinase activity • positive regulation of interleukin-12 biosynthetic process • innate immune response • positive regulation of interleukin-6 biosynthetic process • bone resorption • positive regulation of osteoclast differentiation • negative regulation of transcription, DNA-templated • positive regulation of transcription from RNA polymerase II promoter • neurotrophin TRK receptor signaling pathway • cell development • positive regulation of smooth muscle cell proliferation • T cell receptor signaling pathway • positive regulation of T cell activation • regulation of immunoglobulin secretion • positive regulation of sequence-specific DNA binding transcription factor activity • positive regulation of NF-kappaB transcription factor activity • stress-activated MAPK cascade • protein autoubiquitination • nucleotide-binding oligomerization domain containing signaling pathway • interleukin-1-mediated signaling pathway • protein K63-linked ubiquitination • response to interleukin-1 • cellular response to lipopolysaccharide • apoptotic signaling pathway • positive regulation of transcription regulatory region DNA binding Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	7189	22034
Ensembl	ENSG00000175104	ENSMUSG00000027164
UniProt	Q9Y4K3	P70196
RefSeq (mRNA)	NM_004620	NM_001303273
RefSeq (protein)	NP_004611	NP_001290202
Location (UCSC)	Chr 11: 36.49 – 36.51 Mb	Chr 2: 101.68 – 101.7 Mb
PubMed search

TRAF6 is a TRAF human protein.

Function

The protein encoded by this gene is a member of the TNF receptor associated factor (TRAF) protein family. TRAF proteins are associated with, and mediate signal transduction from members of the TNF receptor superfamily. This protein mediates the signaling not only from the members of the TNF receptor superfamily, but also from the members of the Toll/IL-1 family. Signals from receptors such as CD40, TNFSF11/TRANCE/RANKL and IL-1 have been shown to be mediated by this protein. This protein also interacts with various protein kinases including IRAK1/IRAK, SRC and PKCzeta, which provides a link between distinct signaling pathways. This protein functions as a signal transducer in the NF-kappaB pathway that activates IkappaB kinase (IKK) in response to proinflammatory cytokines. The interaction of this protein with UBE2N/UBC13, and UBE2V1/UEV1A, which are ubiquitin conjugating enzymes catalyzing the formation of polyubiquitin chains, has been found to be required for IKK activation by this protein. Two alternatively spliced transcript variants encoding identical proteins have been reported.^[1]

Signaling pathway of toll-like receptors. Dashed grey lines represent unknown associations

Interactions

TRAF6 has been shown to interact with:

• ASK1,^[2][3][4]
• CD40,^[5][6]
• FHL2,^[7]
• HSPB2,^[8]
• IKBKG,^[9][10]
• IRAK1,^{[11][12][13][14][15][16][17][18][19]}
• IRAK2,^[12][13]
• MAP3K7IP1,^[20][21][22]
• MAP3K7IP2,^{[9][19][20][21][23][24]}
• MAP3K7^{[4][19][20][21][22][23][25]}
• PPP4C,^[26]
• RANK,^{[27][28][29][30][31]}
• SDCBP,^[11]
• SIGIRR,^[32]
• Sequestosome 1,^[33]
• TAX1BP1,^[18]
• TNFAIP3,^[34][35]
• TNFRSF13B,^[36]
• UBE2N,^[37] and
• Ubiquitin C.^{[10][24][26][38][39]}

Model organisms

Model organisms have been used in the study of TRAF6 function. A conditional knockout mouse line called Traf6^{tm2a(EUCOMM)Wtsi} was generated at the Wellcome Trust Sanger Institute.^[40] Male and female animals underwent a standardized phenotypic screen^[41] to determine the effects of deletion.^{[42][43][44][45]} Additional screens performed: - In-depth immunological phenotyping^[46]

Traf6 knockout mouse phenotype

Characteristic	Phenotype
All data available at.[41][46]
Peripheral blood leukocytes 6 Weeks	Normal
Insulin	Normal
Haematology 6 Weeks	Normal
Homozygous viability at P14	Abnormal
Recessive lethal study	Abnormal
Body weight	Normal
Neurological assessment	Normal
Grip strength	Normal
Dysmorphology	Normal
Indirect calorimetry	Normal
Glucose tolerance test	Normal
Auditory brainstem response	Normal
DEXA	Normal
Radiography	Normal
Eye morphology	Normal
Clinical chemistry	Normal
Haematology 16 Weeks	Normal
Peripheral blood leukocytes 16 Weeks	Normal
Heart weight	Normal
Salmonella infection	Normal
Cytotoxic T Cell Function	Normal
Spleen Immunophenotyping	Normal
Mesenteric Lymph Node Immunophenotyping	Normal
Epidermal Immune Composition	Normal

References

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3. Hoeflich KP, Yeh WC, Yao Z, Mak TW, Woodgett JR (October 1999). "Mediation of TNF receptor-associated factor effector functions by apoptosis signal-regulating kinase-1 (ASK1)". Oncogene 18 (42): 5814–20. doi:10.1038/sj.onc.1202975. PMID 10523862.
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5. Tsukamoto N, Kobayashi N, Azuma S, Yamamoto T, Inoue J (February 1999). "Two differently regulated nuclear factor kappaB activation pathways triggered by the cytoplasmic tail of CD40". Proc. Natl. Acad. Sci. U.S.A. 96 (4): 1234–9. doi:10.1073/pnas.96.4.1234. PMC 15446. PMID 9990007.
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7. Bai S, Zha J, Zhao H, Ross FP, Teitelbaum SL (November 2008). "Tumor necrosis factor receptor-associated factor 6 is an intranuclear transcriptional coactivator in osteoclasts". J. Biol. Chem. 283 (45): 30861–7. doi:10.1074/jbc.M802525200. PMC 2662164. PMID 18768464.
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16. Takatsuna H, Kato H, Gohda J, Akiyama T, Moriya A, Okamoto Y, Yamagata Y, Otsuka M, Umezawa K, Semba K, Inoue J (April 2003). "Identification of TIFA as an adapter protein that links tumor necrosis factor receptor-associated factor 6 (TRAF6) to interleukin-1 (IL-1) receptor-associated kinase-1 (IRAK-1) in IL-1 receptor signaling". J. Biol. Chem. 278 (14): 12144–50. doi:10.1074/jbc.M300720200. PMID 12566447.
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18. Ling L, Goeddel DV (August 2000). "T6BP, a TRAF6-interacting protein involved in IL-1 signaling". Proc. Natl. Acad. Sci. U.S.A. 97 (17): 9567–72. doi:10.1073/pnas.170279097. PMC 16905. PMID 10920205.
19. Takaesu G, Ninomiya-Tsuji J, Kishida S, Li X, Stark GR, Matsumoto K (April 2001). "Interleukin-1 (IL-1) receptor-associated kinase leads to activation of TAK1 by inducing TAB2 translocation in the IL-1 signaling pathway". Mol. Cell. Biol. 21 (7): 2475–84. doi:10.1128/MCB.21.7.2475-2484.2001. PMC 86880. PMID 11259596.
20. Takaesu G, Kishida S, Hiyama A, Yamaguchi K, Shibuya H, Irie K, Ninomiya-Tsuji J, Matsumoto K (April 2000). "TAB2, a novel adaptor protein, mediates activation of TAK1 MAPKKK by linking TAK1 to TRAF6 in the IL-1 signal transduction pathway". Mol. Cell 5 (4): 649–58. doi:10.1016/s1097-2765(00)80244-0. PMID 10882101.
21. Walsh MC, Kim GK, Maurizio PL, Molnar EE, Choi Y. Unutmaz D, ed. "TRAF6 autoubiquitination-independent activation of the NFkappaB and MAPK pathways in response to IL-1 and RANKL". PLoS ONE 3 (12): e4064. doi:10.1371/journal.pone.0004064. PMC 2603309. PMID 19112497.
22. Ninomiya-Tsuji J, Kishimoto K, Hiyama A, Inoue J, Cao Z, Matsumoto K (March 1999). "The kinase TAK1 can activate the NIK-I kappaB as well as the MAP kinase cascade in the IL-1 signalling pathway". Nature 398 (6724): 252–6. doi:10.1038/18465. PMID 10094049.
23. Ishitani T, Takaesu G, Ninomiya-Tsuji J, Shibuya H, Gaynor RB, Matsumoto K (Dec 2003). "Role of the TAB2-related protein TAB3 in IL-1 and TNF signaling". EMBO J. 22 (23): 6277–88. doi:10.1093/emboj/cdg605. PMC 291846. PMID 14633987.
24. Ma Q, Zhou L, Shi H, Huo K (June 2008). "NUMBL interacts with TAB2 and inhibits TNFalpha and IL-1beta-induced NF-kappaB activation". Cell. Signal. 20 (6): 1044–51. doi:10.1016/j.cellsig.2008.01.015. PMID 18299187.
25. Sorrentino A, Thakur N, Grimsby S, Marcusson A, von Bulow V, Schuster N, Zhang S, Heldin CH, Landström M (October 2008). "The type I TGF-beta receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner". Nat. Cell Biol. 10 (10): 1199–207. doi:10.1038/ncb1780. PMID 18758450.
26. Chen L, Dong W, Zou T, Ouyang L, He G, Liu Y, Qi Y (August 2008). "Protein phosphatase 4 negatively regulates LPS cascade by inhibiting ubiquitination of TRAF6". FEBS Lett. 582 (19): 2843–9. doi:10.1016/j.febslet.2008.07.014. PMID 18634786.
27. Mizukami J, Takaesu G, Akatsuka H, Sakurai H, Ninomiya-Tsuji J, Matsumoto K, Sakurai N (February 2002). "Receptor activator of NF-kappaB ligand (RANKL) activates TAK1 mitogen-activated protein kinase kinase kinase through a signaling complex containing RANK, TAB2, and TRAF6". Mol. Cell. Biol. 22 (4): 992–1000. doi:10.1128/mcb.22.4.992-1000.2002. PMC 134634. PMID 11809792.
28. Darnay BG, Haridas V, Ni J, Moore PA, Aggarwal BB (August 1998). "Characterization of the intracellular domain of receptor activator of NF-kappaB (RANK). Interaction with tumor necrosis factor receptor-associated factors and activation of NF-kappab and c-Jun N-terminal kinase". J. Biol. Chem. 273 (32): 20551–5. doi:10.1074/jbc.273.32.20551. PMID 9685412.
29. Darnay BG, Ni J, Moore PA, Aggarwal BB (March 1999). "Activation of NF-kappaB by RANK requires tumor necrosis factor receptor-associated factor (TRAF) 6 and NF-kappaB-inducing kinase. Identification of a novel TRAF6 interaction motif". J. Biol. Chem. 274 (12): 7724–31. doi:10.1074/jbc.274.12.7724. PMID 10075662.
30. Galibert L, Tometsko ME, Anderson DM, Cosman D, Dougall WC (Dec 1998). "The involvement of multiple tumor necrosis factor receptor (TNFR)-associated factors in the signaling mechanisms of receptor activator of NF-kappaB, a member of the TNFR superfamily". J. Biol. Chem. 273 (51): 34120–7. doi:10.1074/jbc.273.51.34120. PMID 9852070.
31. Kim HH, Lee DE, Shin JN, Lee YS, Jeon YM, Chung CH, Ni J, Kwon BS, Lee ZH (January 1999). "Receptor activator of NF-kappaB recruits multiple TRAF family adaptors and activates c-Jun N-terminal kinase". FEBS Lett. 443 (3): 297–302. doi:10.1016/s0014-5793(98)01731-1. PMID 10025951.
32. Wald D, Qin J, Zhao Z, Qian Y, Naramura M, Tian L, Towne J, Sims JE, Stark GR, Li X (September 2003). "SIGIRR, a negative regulator of Toll-like receptor-interleukin 1 receptor signaling". Nat. Immunol. 4 (9): 920–7. doi:10.1038/ni968. PMID 12925853.
33. Sanz L, Diaz-Meco MT, Nakano H, Moscat J (April 2000). "The atypical PKC-interacting protein p62 channels NF-kappaB activation by the IL-1-TRAF6 pathway". EMBO J. 19 (7): 1576–86. doi:10.1093/emboj/19.7.1576. PMC 310227. PMID 10747026.
34. Heyninck K, Beyaert R (January 1999). "The cytokine-inducible zinc finger protein A20 inhibits IL-1-induced NF-kappaB activation at the level of TRAF6". FEBS Lett. 442 (2-3): 147–50. doi:10.1016/s0014-5793(98)01645-7. PMID 9928991.
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Further reading

• Wajant H, Henkler F, Scheurich P (2001). "The TNF-receptor-associated factor family: scaffold molecules for cytokine receptors, kinases and their regulators". Cell. Signal. 13 (6): 389–400. doi:10.1016/S0898-6568(01)00160-7. PMID 11384837.
• Bradley JR, Pober JS (2001). "Tumor necrosis factor receptor-associated factors (TRAFs)". Oncogene 20 (44): 6482–91. doi:10.1038/sj.onc.1204788. PMID 11607847.
• Tanaka S, Nakamura K, Takahasi N, Suda T (2006). "Role of RANKL in physiological and pathological bone resorption and therapeutics targeting the RANKL-RANK signaling system". Immunol. Rev. 208: 30–49. doi:10.1111/j.0105-2896.2005.00327.x. PMID 16313339.

External links

• TRAF6 at the US National Library of Medicine Medical Subject Headings (MeSH)