ID TRAF6_MOUSE Reviewed; 530 AA. AC P70196; Q6P9M0; Q8BLV2; DT 09-MAY-2003, integrated into UniProtKB/Swiss-Prot. DT 09-FEB-2010, sequence version 2. DT 02-SEP-2026, entry version 234. DE RecName: Full=TNF receptor-associated factor 6; DE EC=2.3.2.27; DE AltName: Full=E3 ubiquitin-protein ligase TRAF6; DE AltName: Full=RING-type E3 ubiquitin transferase TRAF6 {ECO:0000305}; GN Name=Traf6; OS Mus musculus (Mouse). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Mus; Mus. OX NCBI_TaxID=10090; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RC STRAIN=C57BL/Kaplan; TISSUE=T-cell lymphoma; RX PubMed=8910514; DOI=10.1074/jbc.271.46.28745; RA Ishida T., Mizushima S., Azuma S., Kobayashi N., Tojo T., Suzuki K., RA Aizawa S., Watanabe T., Mosialos G., Kieff E., Yamamoto T., Inoue J.; RT "Identification of TRAF6, a novel tumor necrosis factor receptor-associated RT factor protein that mediates signaling from an amino-terminal domain of the RT CD40 cytoplasmic region."; RL J. Biol. Chem. 271:28745-28748(1996). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). RC STRAIN=C57BL/6J; TISSUE=Aorta, and Vein; RX PubMed=16141072; DOI=10.1126/science.1112014; RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J., RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.; RT "The transcriptional landscape of the mammalian genome."; RL Science 309:1559-1563(2005). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.; RL Submitted (JAN-2009) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC STRAIN=C57BL/6J; TISSUE=Brain; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [5] RP DISRUPTION PHENOTYPE, AND FUNCTION. RX PubMed=10421844; DOI=10.1046/j.1365-2443.1999.00265.x; RA Naito A., Azuma S., Tanaka S., Miyazaki T., Takaki S., Takatsu K., RA Nakao K., Nakamura K., Katsuki M., Yamamoto T., Inoue J.; RT "Severe osteopetrosis, defective interleukin-1 signalling and lymph node RT organogenesis in TRAF6-deficient mice."; RL Genes Cells 4:353-362(1999). RN [6] RP DISRUPTION PHENOTYPE, AND FUNCTION. RX PubMed=10215628; DOI=10.1101/gad.13.8.1015; RA Lomaga M.A., Yeh W.C., Sarosi I., Duncan G.S., Furlonger C., Ho A., RA Morony S., Capparelli C., Van G., Kaufman S., van der Heiden A., Itie A., RA Wakeham A., Khoo W., Sasaki T., Cao Z., Penninger J.M., Paige C.J., RA Lacey D.L., Dunstan C.R., Boyle W.J., Goeddel D.V., Mak T.W.; RT "TRAF6 deficiency results in osteopetrosis and defective interleukin-1, RT CD40, and LPS signaling."; RL Genes Dev. 13:1015-1024(1999). RN [7] RP INTERACTION WITH SQSTM1 AND PRKCZ. RX PubMed=10747026; DOI=10.1093/emboj/19.7.1576; RA Sanz L., Diaz-Meco M.T., Nakano H., Moscat J.; RT "The atypical PKC-interacting protein p62 channels NF-kappaB activation by RT the IL-1-TRAF6 pathway."; RL EMBO J. 19:1576-1586(2000). RN [8] RP INTERACTION WITH IL17R. RX PubMed=10748240; DOI=10.1084/jem.191.7.1233; RA Schwandner R., Yamaguchi K., Cao Z.; RT "Requirement of tumor necrosis factor receptor-associated factor (TRAF)6 in RT interleukin 17 signal transduction."; RL J. Exp. Med. 191:1233-1240(2000). RN [9] RP INTERACTION WITH SQSTM1; PRKCZ AND NGFR. RX PubMed=11244088; DOI=10.1074/jbc.c000869200; RA Wooten M.W., Seibenhener M.L., Mamidipudi V., Diaz-Meco M.T., Barker P.A., RA Moscat J.; RT "The atypical protein kinase C-interacting protein p62 is a scaffold for RT NF-kappaB activation by nerve growth factor."; RL J. Biol. Chem. 276:7709-7712(2001). RN [10] RP DISRUPTION PHENOTYPE. RX PubMed=12060722; DOI=10.1073/pnas.132636999; RA Naito A., Yoshida H., Nishioka E., Satoh M., Azuma S., Yamamoto T., RA Nishikawa S., Inoue J.; RT "TRAF6-deficient mice display hypohidrotic ectodermal dysplasia."; RL Proc. Natl. Acad. Sci. U.S.A. 99:8766-8771(2002). RN [11] RP FUNCTION, AND INTERACTION WITH CD40 AND MAP3K8. RX PubMed=12881420; DOI=10.1093/emboj/cdg386; RA Eliopoulos A.G., Wang C.C., Dumitru C.D., Tsichlis P.N.; RT "Tpl2 transduces CD40 and TNF signals that activate ERK and regulates IgE RT induction by CD40."; RL EMBO J. 22:3855-3864(2003). RN [12] RP DISRUPTION PHENOTYPE, AND FUNCTION. RX PubMed=14499111; DOI=10.1016/s1074-7613(03)00230-9; RA Kobayashi T., Walsh P.T., Walsh M.C., Speirs K.M., Chiffoleau E., RA King C.G., Hancock W.W., Caamano J.H., Hunter C.A., Scott P., Turka L.A., RA Choi Y.; RT "TRAF6 is a critical factor for dendritic cell maturation and RT development."; RL Immunity 19:353-363(2003). RN [13] RP DISRUPTION PHENOTYPE, AND FUNCTION. RX PubMed=15322147; DOI=10.4049/jimmunol.173.5.2913; RA Gohda J., Matsumura T., Inoue J.; RT "TNFR-associated factor (TRAF) 6 is essential for MyD88-dependent pathway RT but not toll/IL-1 receptor domain-containing adapter-inducing IFN-beta RT (TRIF)-dependent pathway in TLR signaling."; RL J. Immunol. 173:2913-2917(2004). RN [14] RP UBIQUITINATION. RX PubMed=16079148; DOI=10.1074/jbc.c500237200; RA Wooten M.W., Geetha T., Seibenhener M.L., Babu J.R., Diaz-Meco M.T., RA Moscat J.; RT "The p62 scaffold regulates nerve growth factor-induced NF-kappaB RT activation by influencing TRAF6 polyubiquitination."; RL J. Biol. Chem. 280:35625-35629(2005). RN [15] RP DISRUPTION PHENOTYPE. RX PubMed=15705807; DOI=10.1126/science.1105677; RA Akiyama T., Maeda S., Yamane S., Ogino K., Kasai M., Kajiura F., RA Matsumoto M., Inoue J.; RT "Dependence of self-tolerance on TRAF6-directed development of thymic RT stroma."; RL Science 308:248-251(2005). RN [16] RP IDENTIFICATION IN COMPLEX WITH IRAK1; IRAK4; MYD88 AND PELI1. RX PubMed=16951688; DOI=10.1038/ni1383; RA Choi K.C., Lee Y.S., Lim S., Choi H.K., Lee C.H., Lee E.K., Hong S., RA Kim I.H., Kim S.J., Park S.H.; RT "Smad6 negatively regulates interleukin 1-receptor-Toll-like receptor RT signaling through direct interaction with the adapter Pellino-1."; RL Nat. Immunol. 7:1057-1065(2006). RN [17] RP DISRUPTION PHENOTYPE, AND FUNCTION. RX PubMed=17633018; DOI=10.1007/978-0-387-70630-6_6; RA Inoue J., Gohda J., Akiyama T.; RT "Characteristics and biological functions of TRAF6."; RL Adv. Exp. Med. Biol. 597:72-79(2007). RN [18] RP FUNCTION, AND INTERACTION WITH LIMD1. RX PubMed=17092936; DOI=10.1074/jbc.m607399200; RA Feng Y., Zhao H., Luderer H.F., Epple H., Faccio R., Ross F.P., RA Teitelbaum S.L., Longmore G.D.; RT "The LIM protein, Limd1, regulates AP-1 activation through an interaction RT with Traf6 to influence osteoclast development."; RL J. Biol. Chem. 282:39-48(2007). RN [19] RP INTERACTION WITH TRAFD1. RX PubMed=18849341; DOI=10.1074/jbc.m806923200; RA Sanada T., Takaesu G., Mashima R., Yoshida R., Kobayashi T., Yoshimura A.; RT "FLN29 deficiency reveals its negative regulatory role in the Toll-like RT receptor (TLR) and retinoic acid-inducible gene I (RIG-I)-like helicase RT signaling pathway."; RL J. Biol. Chem. 283:33858-33864(2008). RN [20] RP INTERACTION WITH RSAD2, AND SUBCELLULAR LOCATION. RX PubMed=21435586; DOI=10.1016/j.immuni.2011.03.010; RA Saitoh T., Satoh T., Yamamoto N., Uematsu S., Takeuchi O., Kawai T., RA Akira S.; RT "Antiviral protein Viperin promotes Toll-like receptor 7- and Toll-like RT receptor 9-mediated type I interferon production in plasmacytoid dendritic RT cells."; RL Immunity 34:352-363(2011). RN [21] RP INTERACTION WITH GPS2. RX PubMed=22424771; DOI=10.1016/j.molcel.2012.01.025; RA Cardamone M.D., Krones A., Tanasa B., Taylor H., Ricci L., Ohgi K.A., RA Glass C.K., Rosenfeld M.G., Perissi V.; RT "A protective strategy against hyperinflammatory responses requiring the RT nontranscriptional actions of GPS2."; RL Mol. Cell 46:91-104(2012). RN [22] RP UBIQUITINATION AT LYS-327, AND MUTAGENESIS OF LYS-327 AND TRP-363. RX PubMed=23542741; DOI=10.1038/ni.2565; RA Chen B.B., Coon T.A., Glasser J.R., McVerry B.J., Zhao J., Zhao Y., Zou C., RA Ellis B., Sciurba F.C., Zhang Y., Mallampalli R.K.; RT "A combinatorial F box protein directed pathway controls TRAF adaptor RT stability to regulate inflammation."; RL Nat. Immunol. 14:470-479(2013). RN [23] RP UBIQUITINATION. RX PubMed=25026888; DOI=10.1038/ncomms5434; RA Su X., Min S., Cao S., Yan H., Zhao Y., Li H., Chai L., Mei S., Yang J., RA Zhang Y., Zhang Z., Liu F., Sun W., Che Y., Yang R.; RT "LRRC19 expressed in the kidney induces TRAF2/6-mediated signals to prevent RT infection by uropathogenic bacteria."; RL Nat. Commun. 5:4434-4434(2014). RN [24] RP INTERACTION WITH TOXOPLASMA GRA7. RX PubMed=26553469; DOI=10.1128/iai.00734-15; RA Yang C.S., Yuk J.M., Lee Y.H., Jo E.K.; RT "Toxoplasma gondii GRA7-Induced TRAF6 Activation Contributes to Host RT Protective Immunity."; RL Infect. Immun. 84:339-350(2016). RN [25] RP INTERACTION WITH WDFY3. RX PubMed=27330028; DOI=10.1016/j.jaut.2016.06.004; RA Wu D.J., Gu R., Sarin R., Zavodovskaya R., Chen C.P., Christiansen B.A., RA Adamopoulos I.E.; RT "Autophagy-linked FYVE containing protein WDFY3 interacts with TRAF6 and RT modulates RANKL-induced osteoclastogenesis."; RL J. Autoimmun. 73:73-84(2016). CC -!- FUNCTION: E3 ubiquitin ligase that, together with UBE2N and UBE2V1, CC mediates the synthesis of 'Lys-63'-linked-polyubiquitin chains CC conjugated to proteins, such as ECSIT, IKBKG, IRAK1, AKT1 and AKT2 CC (PubMed:15322147, PubMed:17633018). Also mediates ubiquitination of CC free/unanchored polyubiquitin chain that leads to MAP3K7 activation (By CC similarity). Leads to the activation of NF-kappa-B and JUN. Seems to CC also play a role in dendritic cells (DCs) maturation and/or activation CC (PubMed:14499111). Represses c-Myb-mediated transactivation, in B- CC lymphocytes (By similarity). Adapter protein that seems to play a role CC in signal transduction initiated via TNF receptor, IL-1 receptor and CC IL-17 receptor (PubMed:10215628, PubMed:10421844). Regulates osteoclast CC differentiation by mediating the activation of adapter protein complex CC 1 (AP-1) and NF-kappa-B, in response to RANK-L stimulation CC (PubMed:10421844, PubMed:17092936). Together with MAP3K8, mediates CD40 CC signals that activate ERK in B-cells and macrophages, and thus may play CC a role in the regulation of immunoglobulin production CC (PubMed:12881420). Acts as a regulator of the JNK and NF-kappa-B CC signaling pathways by initiating assembly of heterotypic 'Lys- CC 63'-/'Lys-48'-linked branched ubiquitin chains that are then recognized CC by TAB2: TRAF6 catalyzes initial 'Lys-63'-linked-polyubiquitin chains CC that are then branched via 'Lys-48'-linked polyubiquitin by HUWE1 (By CC similarity). 'Lys-63'-/'Lys-48'-linked branched ubiquitin chains CC protect 'Lys-63'-linkages from CYLD deubiquitination (By similarity). CC Also participates in the TCR signaling by ubiquitinating LAT (By CC similarity). {ECO:0000250|UniProtKB:Q9Y4K3, CC ECO:0000269|PubMed:10215628, ECO:0000269|PubMed:10421844, CC ECO:0000269|PubMed:12881420, ECO:0000269|PubMed:14499111, CC ECO:0000269|PubMed:15322147, ECO:0000269|PubMed:17092936, CC ECO:0000269|PubMed:17633018}. CC -!- CATALYTIC ACTIVITY: CC Reaction=S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + CC [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L- CC cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.; CC EC=2.3.2.27; Evidence={ECO:0000250|UniProtKB:Q9Y4K3}; CC -!- PATHWAY: Protein modification; protein ubiquitination. CC {ECO:0000250|UniProtKB:Q9Y4K3}. CC -!- SUBUNIT: Homotrimer (By similarity). Homooligomer (By similarity). N- CC terminal region is dimeric while C-terminal region is trimeric; maybe CC providing a mode of oligomerization. Upon IL1B treatment, forms a CC complex with PELI1, IRAK1, IRAK4 and MYD88; this complex recruits CC MAP3K7/TAK1, TAB1 and TAB2 to mediate NF-kappa-B activation. Direct CC binding of SMAD6 to PELI1 prevents the complex formation and hence CC negatively regulates IL1R-TLR signaling and eventually NF-kappa-B- CC mediated gene expression. Binds to TNFRSF5/CD40 and TNFRSF11A/RANK (By CC similarity). Associates with NGFR, TNFRSF17, IRAK2, IRAK3, PELI2, CC PELI3, RIPK2, MAP3K1, MAP3K5, MAP3K14, CSK, TRAF, TRAF-interacting CC protein TRIP and TNF receptor associated protein TDP2. Binds UBE2V1. CC Interacts with MAVS/IPS1. Interacts with TAX1BP1; this interaction CC mediates deubiquitination of TRAF6 and inhibition of NF-kappa-B CC activation (By similarity). Interacts with IL17R. Interacts with SQSTM1 CC bridging NTRK1 and NGFR. Forms a ternary complex with SQSTM1 and PRKCZ. CC Interacts with IL1RL1. Interacts with AJUBA (By similarity). Interacts CC with TRAFD1. Interacts with TICAM2. Interacts with ZFAND5. Interacts CC with ARRB1 and ARRB2 (By similarity). Interacts with MAP3K7 and CC TAB1/MAP3K7IP1; during IL-1 signaling. Interacts with UBE2N. Interacts CC with TGFBR1, HDAC1 and RANGAP1. Interacts with AKT1, AKT2 and AKT3. CC Interacts (via TRAF domains) with NUMBL (via C-terminal) (By CC similarity). Interacts (via TRAF domains) with DYNC2I2 (via WD CC domains). Interacts with RBCK1 (By similarity). Interacts with LIMD1 CC (via LIM domains). Interacts with RSAD2/viperin. Interacts with IFIT3 CC (via N-terminus) (By similarity). Interacts (via C-terminus) with CC EIF2AK2/PKR (via the kinase catalytic domain). Interacts with CARD14 CC (By similarity). Interacts with CD40 and MAP3K8; the interaction is CC required for ERK activation. Interacts with TICAM1 and this interaction CC is enhanced in the presence of WDFY1 (By similarity). Interacts with CC TANK; this interaction increases in response to DNA damage (By CC similarity). Interacts with USP10; this interaction increases in CC response to DNA damage (By similarity). Interacts with ZC3H12A; this CC interaction increases in response to DNA damage and is stimulated by CC TANK (By similarity). Interacts with WDFY3 (PubMed:27330028). Interacts CC with TRIM13 (By similarity). Interacts with GPS2 (PubMed:22424771). CC Interacts (via C-terminus) with SASH1 (By similarity). Interacts with CC LRRC19 (By similarity). Interacts with IL17RA and TRAF3IP2. Interacts CC with TOMM70 (By similarity). Interacts with AMBRA1; interaction is CC required to mediate 'Lys-63'-linked ubiquitination of ULK1 (By CC similarity). Interacts with CRBN; this interaction inhibits TLR4- CC mediated signaling by preventing TRAF6-mediated ubiquitination of ECSIT CC (By similarity). Interacts with STING1; interaction takes place in CC response to virus infection and promotes activation of NF-kappa-B CC signaling (By similarity). {ECO:0000250|UniProtKB:Q9Y4K3, CC ECO:0000269|PubMed:10747026, ECO:0000269|PubMed:10748240, CC ECO:0000269|PubMed:11244088, ECO:0000269|PubMed:12881420, CC ECO:0000269|PubMed:16951688, ECO:0000269|PubMed:17092936, CC ECO:0000269|PubMed:18849341, ECO:0000269|PubMed:21435586, CC ECO:0000269|PubMed:22424771, ECO:0000269|PubMed:27330028}. CC -!- SUBUNIT: (Microbial infection) Interacts (via N-terminal RING domain) CC with Toxoplasma gondii GRA7; the interaction plays a role in GRA7- CC induced pro-inflammatory cytokine production in mouse macrophages. CC {ECO:0000269|PubMed:26553469}. CC -!- INTERACTION: CC P70196; P27512: Cd40; NbExp=2; IntAct=EBI-448028, EBI-525742; CC P70196; Q9QZH6: Ecsit; NbExp=5; IntAct=EBI-448028, EBI-527020; CC P70196; Q9EQY0: Ern1; NbExp=6; IntAct=EBI-448028, EBI-5480799; CC P70196; P17879: Hspa1b; NbExp=3; IntAct=EBI-448028, EBI-397360; CC P70196; Q62406-1: Irak1; NbExp=4; IntAct=EBI-448028, EBI-488313; CC P70196; Q8K4B2: Irak3; NbExp=3; IntAct=EBI-448028, EBI-646179; CC P70196; Q61084: Map3k3; NbExp=5; IntAct=EBI-448028, EBI-446250; CC P70196; P22366: Myd88; NbExp=4; IntAct=EBI-448028, EBI-525108; CC P70196; Q62227: Nr0b2; NbExp=5; IntAct=EBI-448028, EBI-4310440; CC P70196; P35235: Ptpn11; NbExp=2; IntAct=EBI-448028, EBI-397236; CC P70196; Q793I8: Tifa; NbExp=2; IntAct=EBI-448028, EBI-524817; CC P70196; O35305: Tnfrsf11a; NbExp=2; IntAct=EBI-448028, EBI-647362; CC P70196; Q8C0E5: Traf3ip2; NbExp=3; IntAct=EBI-448028, EBI-530713; CC P70196; Q8N7N6: Traf3ip2; NbExp=4; IntAct=EBI-448028, EBI-646165; CC P70196; Q3UDK1: Trafd1; NbExp=2; IntAct=EBI-448028, EBI-1396948; CC P70196; P62991: Ubc; NbExp=5; IntAct=EBI-448028, EBI-413074; CC P70196; Q96CG3: TIFA; Xeno; NbExp=4; IntAct=EBI-448028, EBI-740711; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q9Y4K3}. CC Cytoplasm, cell cortex {ECO:0000250|UniProtKB:Q9Y4K3}. Nucleus CC {ECO:0000250|UniProtKB:Q9Y4K3}. Lipid droplet CC {ECO:0000269|PubMed:21435586}. Note=RSAD2/viperin recruits it to the CC lipid droplet. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=P70196-1; Sequence=Displayed; CC Name=2; CC IsoId=P70196-2; Sequence=VSP_007404, VSP_007405; CC -!- TISSUE SPECIFICITY: Highly expressed in brain, lung, liver, skeletal CC muscle, and kidney; lower expression in heart, spleen, and testis. CC -!- DOMAIN: The coiled coil domain mediates homo- and hetero- CC oligomerization. CC -!- DOMAIN: The MATH/TRAF domain binds to receptor cytoplasmic domains. CC -!- PTM: Sumoylated on Lys-124, Lys-142 and Lys-461 with SUMO1. Sumoylated CC on Lys-461 by TRIM28 in the nucleus, SUMOylation regulates the nucleo- CC cytoplasmic shuttling of TRAF6. {ECO:0000250|UniProtKB:Q9Y4K3}. CC -!- PTM: Polyubiquitinated on Lys-124 by TRAF3IP2; after cell stimulation CC with IL17A (By similarity). Polyubiquitinated; after cell stimulation CC with IL1B or TGFB. This ligand-induced cell stimulation leads to CC dimerization/oligomerization of TRAF6 molecules, followed by auto- CC ubiquitination which involves UBE2N and UBE2V1 and leads to TRAF6 CC activation. This 'Lys-63' site-specific poly-ubiquitination appears to CC be associated with the activation of signaling molecules. Endogenous CC autoubiquitination occurs only for the cytoplasmic form. CC Deubiquitinated by USP10 in a TANK-dependent manner, leading to the CC negative regulation of NF-kappa-B signaling upon DNA damage. LRRC19 CC induces 'Lys-63' ubiquitination (PubMed:25026888). Ubiquitinated at CC Lys-327 by the SCF(FBXL2) complex, leading to its degradation by the CC proteasome (PubMed:23542741). {ECO:0000250|UniProtKB:Q9Y4K3, CC ECO:0000269|PubMed:23542741, ECO:0000269|PubMed:25026888}. CC -!- DISRUPTION PHENOTYPE: Abrogation of IL-1-induced activation of NF- CC kappa-B, MAPK8/JNK and MAPK14/p38. Animals appear normal at birth but CC become smaller after one week. Show runting, failure of tooth eruption CC and die after three weeks. Exhibit severe osteopetrosis, thymic CC atrophy, lymph node deficiency, splenomegaly, and have alopecia and CC lack sweat glands. {ECO:0000269|PubMed:10215628, CC ECO:0000269|PubMed:10421844, ECO:0000269|PubMed:12060722, CC ECO:0000269|PubMed:14499111, ECO:0000269|PubMed:15322147, CC ECO:0000269|PubMed:15705807, ECO:0000269|PubMed:17633018}. CC -!- SIMILARITY: Belongs to the TNF receptor-associated factor family. A CC subfamily. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; D84655; BAA12705.1; -; mRNA. DR EMBL; AK041172; BAC30850.1; -; mRNA. DR EMBL; AK155434; BAE33263.1; -; mRNA. DR EMBL; AL929571; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH466519; EDL27656.1; -; Genomic_DNA. DR EMBL; CH466519; EDL27657.1; -; Genomic_DNA. DR EMBL; BC060705; AAH60705.1; -; mRNA. DR CCDS; CCDS16464.1; -. [P70196-1] DR RefSeq; NP_001290202.1; NM_001303273.1. [P70196-1] DR RefSeq; NP_033450.2; NM_009424.3. [P70196-1] DR AlphaFoldDB; P70196; -. DR BMRB; P70196; -. DR SMR; P70196; -. DR BioGRID; 204307; 114. DR CORUM; P70196; -. DR DIP; DIP-29812N; -. DR FunCoup; P70196; 3572. DR IntAct; P70196; 42. DR MINT; P70196; -. DR STRING; 10090.ENSMUSP00000004949; -. DR iPTMnet; P70196; -. DR PhosphoSitePlus; P70196; -. DR PaxDb; 10090-ENSMUSP00000004949; -. DR PeptideAtlas; P70196; -. DR ProteomicsDB; 258843; -. [P70196-1] DR ProteomicsDB; 258844; -. [P70196-2] DR Pumba; P70196; -. DR Antibodypedia; 3895; 582 antibodies from 48 providers. DR DNASU; 22034; -. DR Ensembl; ENSMUST00000004949.8; ENSMUSP00000004949.8; ENSMUSG00000027164.9. [P70196-1] DR GeneID; 22034; -. DR KEGG; mmu:22034; -. DR UCSC; uc008lhl.2; mouse. [P70196-2] DR UCSC; uc008lhm.2; mouse. [P70196-1] DR AGR; MGI:108072; -. DR CTD; 7189; -. DR MGI; MGI:108072; Traf6. DR VEuPathDB; HostDB:ENSMUSG00000027164; -. DR eggNOG; KOG0297; Eukaryota. DR GeneTree; ENSGT00940000155426; -. DR HOGENOM; CLU_021061_5_0_1; -. DR InParanoid; P70196; -. DR OMA; FMHLQAL; -. DR OrthoDB; 6475149at2759; -. DR PhylomeDB; P70196; -. DR Reactome; R-MMU-1257604; PIP3 activates AKT signaling. [P70196-1] DR Reactome; R-MMU-166058; MyD88:MAL(TIRAP) cascade initiated on plasma membrane. [P70196-1] DR Reactome; R-MMU-168638; NOD1/2 Signaling Pathway. [P70196-1] DR Reactome; R-MMU-193692; Regulated proteolysis of p75NTR. [P70196-1] DR Reactome; R-MMU-202424; Downstream TCR signaling. [P70196-1] DR Reactome; R-MMU-205043; NRIF signals cell death from the nucleus. [P70196-1] DR Reactome; R-MMU-209543; p75NTR recruits signalling complexes. [P70196-1] DR Reactome; R-MMU-209560; NF-kB is activated and signals survival. [P70196-1] DR Reactome; R-MMU-2871837; FCERI mediated NF-kB activation. [P70196-1] DR Reactome; R-MMU-445989; TAK1-dependent IKK and NF-kappa-B activation. [P70196-1] DR Reactome; R-MMU-450302; activated TAK1 mediates p38 MAPK activation. [P70196-1] DR Reactome; R-MMU-450321; JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1. [P70196-1] DR Reactome; R-MMU-5607764; CLEC7A (Dectin-1) signaling. [P70196-1] DR Reactome; R-MMU-5689880; Ub-specific processing proteases. [P70196-1] DR Reactome; R-MMU-5689896; Ovarian tumor domain proteases. [P70196-1] DR Reactome; R-MMU-6811558; PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling. [P70196-1] DR Reactome; R-MMU-9020702; Interleukin-1 signaling. [P70196-1] DR Reactome; R-MMU-937039; IRAK1 recruits IKK complex. [P70196-1] DR Reactome; R-MMU-937041; IKK complex recruitment mediated by RIP1. [P70196-1] DR Reactome; R-MMU-937042; IRAK2 mediated activation of TAK1 complex. [P70196-1] DR Reactome; R-MMU-937072; TRAF6-mediated induction of TAK1 complex within TLR4 complex. [P70196-1] DR Reactome; R-MMU-9645460; Alpha-protein kinase 1 signaling pathway. [P70196-1] DR Reactome; R-MMU-975138; TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation. [P70196-1] DR Reactome; R-MMU-975144; IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation. [P70196-1] DR Reactome; R-MMU-975163; IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation. [P70196-1] DR Reactome; R-MMU-9758274; Regulation of NF-kappa B signaling. [P70196-1] DR Reactome; R-MMU-975871; MyD88 cascade initiated on plasma membrane. [P70196-1] DR UniPathway; UPA00143; -. DR BioGRID-ORCS; 22034; 21 hits in 80 CRISPR screens. DR PRO; PR:P70196; -. DR Proteomes; UP000000589; Chromosome 2. DR RNAct; P70196; protein. DR Bgee; ENSMUSG00000027164; Expressed in ileal epithelium and 213 other cell types or tissues. DR GO; GO:0035631; C:CD40 receptor complex; IDA:BHF-UCL. DR GO; GO:0005938; C:cell cortex; IEA:UniProtKB-SubCell. DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB. DR GO; GO:0009898; C:cytoplasmic side of plasma membrane; IDA:BHF-UCL. DR GO; GO:0005829; C:cytosol; IDA:UniProtKB. DR GO; GO:0098978; C:glutamatergic synapse; IDA:SynGO. DR GO; GO:0005811; C:lipid droplet; IDA:UniProtKB. DR GO; GO:0005634; C:nucleus; ISS:UniProtKB. DR GO; GO:0048471; C:perinuclear region of cytoplasm; ISO:GO_Central. DR GO; GO:0005886; C:plasma membrane; ISO:GO_Central. DR GO; GO:0098794; C:postsynapse; ISO:GO_Central. DR GO; GO:0032991; C:protein-containing complex; ISO:GO_Central. DR GO; GO:0000151; C:ubiquitin ligase complex; ISO:GO_Central. DR GO; GO:0042826; F:histone deacetylase binding; ISO:GO_Central. DR GO; GO:0042802; F:identical protein binding; ISO:GO_Central. DR GO; GO:0043422; F:protein kinase B binding; ISO:GO_Central. DR GO; GO:0030674; F:protein-macromolecule adaptor activity; ISO:GO_Central. DR GO; GO:0035591; F:signaling adaptor activity; IBA:GO_Central. DR GO; GO:0005164; F:tumor necrosis factor receptor binding; IEA:InterPro. DR GO; GO:0031624; F:ubiquitin conjugating enzyme binding; ISO:MGI. DR GO; GO:0061630; F:ubiquitin protein ligase activity; IDA:UniProt. DR GO; GO:0004842; F:ubiquitin-protein transferase activity; IDA:UniProtKB. DR GO; GO:0034450; F:ubiquitin-ubiquitin ligase activity; ISO:GO_Central. DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro. DR GO; GO:0032147; P:activation of protein kinase activity; ISO:GO_Central. DR GO; GO:0009887; P:animal organ morphogenesis; IMP:MGI. DR GO; GO:0019886; P:antigen processing and presentation of exogenous peptide antigen via MHC class II; IMP:MGI. DR GO; GO:0140374; P:antiviral innate immune response; ISO:GO_Central. DR GO; GO:0000045; P:autophagosome assembly; ISO:GO_Central. DR GO; GO:0046849; P:bone remodeling; IMP:UniProtKB. DR GO; GO:0045453; P:bone resorption; IMP:UniProtKB. DR GO; GO:0007249; P:canonical NF-kappaB signal transduction; IMP:UniProtKB. DR GO; GO:0023035; P:CD40 signaling pathway; ISO:GO_Central. DR GO; GO:0048468; P:cell development; IMP:MGI. DR GO; GO:0071345; P:cellular response to cytokine stimulus; ISO:GO_Central. DR GO; GO:0071222; P:cellular response to lipopolysaccharide; ISO:MGI. DR GO; GO:0019221; P:cytokine-mediated signaling pathway; ISO:GO_Central. DR GO; GO:0002753; P:cytoplasmic pattern recognition receptor signaling pathway; ISO:GO_Central. DR GO; GO:0042742; P:defense response to bacterium; ISO:GO_Central. DR GO; GO:0006955; P:immune response; IMP:MGI. DR GO; GO:0001701; P:in utero embryonic development; IMP:MGI. DR GO; GO:0045087; P:innate immune response; IBA:GO_Central. DR GO; GO:0070498; P:interleukin-1-mediated signaling pathway; IMP:UniProtKB. DR GO; GO:0097400; P:interleukin-17-mediated signaling pathway; IDA:MGI. DR GO; GO:0038173; P:interleukin-17A-mediated signaling pathway; ISO:GO_Central. DR GO; GO:0038172; P:interleukin-33-mediated signaling pathway; ISO:GO_Central. DR GO; GO:0007254; P:JNK cascade; ISO:GO_Central. DR GO; GO:0031663; P:lipopolysaccharide-mediated signaling pathway; IMP:MGI. DR GO; GO:0009299; P:mRNA transcription; ISO:GO_Central. DR GO; GO:0043011; P:myeloid dendritic cell differentiation; IMP:MGI. DR GO; GO:0043124; P:negative regulation of canonical NF-kappaB signal transduction; ISO:GO_Central. DR GO; GO:0045892; P:negative regulation of DNA-templated transcription; ISO:GO_Central. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; ISO:GO_Central. DR GO; GO:0001843; P:neural tube closure; IMP:UniProtKB. DR GO; GO:0038061; P:non-canonical NF-kappaB signal transduction; ISO:GO_Central. DR GO; GO:0042475; P:odontogenesis of dentin-containing tooth; IMP:MGI. DR GO; GO:0001503; P:ossification; IMP:MGI. DR GO; GO:0030316; P:osteoclast differentiation; IMP:UniProtKB. DR GO; GO:0043123; P:positive regulation of canonical NF-kappaB signal transduction; IMP:UniProtKB. DR GO; GO:0032735; P:positive regulation of interleukin-12 production; IMP:MGI. DR GO; GO:0032743; P:positive regulation of interleukin-2 production; ISO:GO_Central. DR GO; GO:0032755; P:positive regulation of interleukin-6 production; IMP:MGI. DR GO; GO:0046330; P:positive regulation of JNK cascade; ISO:GO_Central. DR GO; GO:1904996; P:positive regulation of leukocyte adhesion to vascular endothelial cell; ISO:GO_Central. DR GO; GO:0031666; P:positive regulation of lipopolysaccharide-mediated signaling pathway; IMP:UniProtKB. DR GO; GO:0045672; P:positive regulation of osteoclast differentiation; ISO:GO_Central. DR GO; GO:0048661; P:positive regulation of smooth muscle cell proliferation; ISO:GO_Central. DR GO; GO:0002726; P:positive regulation of T cell cytokine production; ISO:GO_Central. DR GO; GO:0042102; P:positive regulation of T cell proliferation; IMP:UniProtKB. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; ISO:GO_Central. DR GO; GO:0032481; P:positive regulation of type I interferon production; IDA:UniProt. DR GO; GO:0051865; P:protein autoubiquitination; ISO:GO_Central. DR GO; GO:0141198; P:protein branched polyubiquitination; ISS:UniProtKB. DR GO; GO:0070936; P:protein K48-linked ubiquitination; ISO:GO_Central. DR GO; GO:0070534; P:protein K63-linked ubiquitination; IDA:UniProtKB. DR GO; GO:0000209; P:protein polyubiquitination; IMP:MGI. DR GO; GO:0016567; P:protein ubiquitination; IDA:MGI. DR GO; GO:0042981; P:regulation of apoptotic process; IEA:InterPro. DR GO; GO:0043122; P:regulation of canonical NF-kappaB signal transduction; IBA:GO_Central. DR GO; GO:0002637; P:regulation of immunoglobulin production; IDA:MGI. DR GO; GO:0098696; P:regulation of neurotransmitter receptor localization to postsynaptic specialization membrane; IDA:SynGO. DR GO; GO:0140252; P:regulation protein catabolic process at postsynapse; ISO:GO_Central. DR GO; GO:0070555; P:response to interleukin-1; ISO:GO_Central. DR GO; GO:0007165; P:signal transduction; IDA:MGI. DR GO; GO:0007416; P:synapse assembly; ISO:GO_Central. DR GO; GO:0050852; P:T cell receptor signaling pathway; ISO:GO_Central. DR GO; GO:0042088; P:T-helper 1 type immune response; IMP:MGI. DR GO; GO:0034142; P:toll-like receptor 4 signaling pathway; ISO:GO_Central. DR GO; GO:0034162; P:toll-like receptor 9 signaling pathway; ISO:GO_Central. DR GO; GO:0033209; P:tumor necrosis factor-mediated signaling pathway; ISO:GO_Central. DR CDD; cd03776; MATH_TRAF6; 1. DR CDD; cd16643; mRING-HC-C3HC3D_TRAF6; 1. DR FunFam; 2.60.210.10:FF:000010; TNF receptor-associated factor; 1. DR FunFam; 3.30.40.10:FF:000179; TNF receptor-associated factor; 1. DR FunFam; 3.30.40.10:FF:000211; TNF receptor-associated factor; 1. DR FunFam; 3.30.40.10:FF:000289; TNF receptor-associated factor; 1. DR Gene3D; 2.60.210.10; Apoptosis, Tumor Necrosis Factor Receptor Associated Protein 2, Chain A; 1. DR Gene3D; 3.30.40.10; Zinc/RING finger domain, C3HC4 (zinc finger); 3. DR InterPro; IPR002083; MATH/TRAF_dom. DR InterPro; IPR012227; TNF_rcpt-assoc_TRAF_met. DR InterPro; IPR008974; TRAF-like. DR InterPro; IPR049342; TRAF1-6_MATH_dom. DR InterPro; IPR037309; TRAF6_MATH. DR InterPro; IPR027139; TRAF6_RING-HC. DR InterPro; IPR041310; TRAF6_Z2. DR InterPro; IPR001841; Znf_RING. DR InterPro; IPR013083; Znf_RING/FYVE/PHD. DR InterPro; IPR017907; Znf_RING_CS. DR InterPro; IPR001293; Znf_TRAF. DR PANTHER; PTHR10131; TNF RECEPTOR ASSOCIATED FACTOR; 1. DR PANTHER; PTHR10131:SF152; TNF RECEPTOR-ASSOCIATED FACTOR 6; 1. DR Pfam; PF21355; TRAF-mep_MATH; 1. DR Pfam; PF18048; TRAF6_Z2; 1. DR Pfam; PF13923; zf-C3HC4_2; 1. DR Pfam; PF02176; zf-TRAF; 1. DR PIRSF; PIRSF015614; TRAF; 1. DR SMART; SM00061; MATH; 1. DR SMART; SM00184; RING; 1. DR SUPFAM; SSF57850; RING/U-box; 1. DR SUPFAM; SSF49599; TRAF domain-like; 3. DR PROSITE; PS50144; MATH; 1. DR PROSITE; PS00518; ZF_RING_1; 1. DR PROSITE; PS50089; ZF_RING_2; 1. DR PROSITE; PS50145; ZF_TRAF; 2. PE 1: Evidence at protein level; KW Alternative splicing; Coiled coil; Cytoplasm; DNA damage; Immunity; KW Isopeptide bond; Lipid droplet; Metal-binding; Nucleus; Osteogenesis; KW Reference proteome; Repeat; Transferase; Ubl conjugation; KW Ubl conjugation pathway; Zinc; Zinc-finger. FT CHAIN 1..530 FT /note="TNF receptor-associated factor 6" FT /id="PRO_0000056408" FT DOMAIN 358..507 FT /note="MATH" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00129" FT ZN_FING 70..109 FT /note="RING-type" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00175" FT ZN_FING 150..202 FT /note="TRAF-type 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00207" FT ZN_FING 203..259 FT /note="TRAF-type 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00207" FT REGION 1..362 FT /note="Interaction with TAX1BP1" FT /evidence="ECO:0000250" FT REGION 363..530 FT /note="Interaction with TANK" FT /evidence="ECO:0000250|UniProtKB:Q9Y4K3" FT COILED 299..356 FT /evidence="ECO:0000255" FT CROSSLNK 124 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO); alternate" FT /evidence="ECO:0000250" FT CROSSLNK 124 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin); alternate" FT /evidence="ECO:0000250|UniProtKB:Q9Y4K3" FT CROSSLNK 142 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO)" FT /evidence="ECO:0000250" FT CROSSLNK 327 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:23542741" FT CROSSLNK 461 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO)" FT /evidence="ECO:0000250" FT VAR_SEQ 100..174 FT /note="DAGHKCPVDNEILLENQLFPDNFAKREILSLTVKCPNKGCLQKMELRHLEDH FT QVHCEFALVNCPQCQRPFQKCQV -> YLILRKHGALQQPNVKSMLETGHPKNRQTENT FT GQEHSRMDRNLRQLGSHPSLYYGMNRGLLPCLPTQPPGKLQSP (in isoform 2)" FT /evidence="ECO:0000303|PubMed:16141072" FT /id="VSP_007404" FT VAR_SEQ 175..530 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:16141072" FT /id="VSP_007405" FT MUTAGEN 327 FT /note="K->R: Abolished ubiquitination by the SCF(FBXL2) FT complex." FT /evidence="ECO:0000269|PubMed:23542741" FT MUTAGEN 363 FT /note="W->A: Decreased interaction with FBXL2." FT /evidence="ECO:0000269|PubMed:23542741" FT CONFLICT 251 FT /note="E -> Q (in Ref. 1; BAA12705 and 2; BAC30850)" FT /evidence="ECO:0000305" FT CONFLICT 367 FT /note="N -> K (in Ref. 1; BAA12705 and 2; BAC30850)" FT /evidence="ECO:0000305" SQ SEQUENCE 530 AA; 60070 MW; F8389250425E4E2D CRC64; MSLLNCENSC GSSQSSSDCC AAMAASCSAA VKDDSVSGSA STGNLSSSFM EEIQGYDVEF DPPLESKYEC PICLMALREA VQTPCGHRFC KACIIKSIRD AGHKCPVDNE ILLENQLFPD NFAKREILSL TVKCPNKGCL QKMELRHLED HQVHCEFALV NCPQCQRPFQ KCQVNTHIIE DCPRRQVSCV NCAVSMAYEE KEIHDQSCPL ANIICEYCGT ILIREQMPNH YDLDCPTAPI PCTFSVFGCH EKMQRNHLAR HLQENTQLHM RLLAQAVHNV NLALRPCDAA SPSRGCRPED PNYEETIKQL ESRLVRQDHQ IRELTAKMET QSMYVGELKR TIRTLEDKVA EMEAQQCNGI YIWKIGNFGM HLKSQEEERP VVIHSPGFYT GRPGYKLCMR LHLQLPTAQR CANYISLFVH TMQGEYDSHL PWPFQGTIRL TILDQSEALI RQNHEEVMDA KPELLAFQRP TIPRNPKGFG YVTFMHLEAL RQGTFIKDDT LLVRCEVSTR FDMGGLRKEG FQPRSTDAGV //