TRAF6_MOUSE
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 03-AUG-2022, entry version 215.
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.
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 [23]
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 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:10421844, PubMed:10215628). 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). {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;
CC -!- PATHWAY: Protein modification; protein ubiquitination.
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 (By similarity).
CC Interacts with IL17R. Interacts with SQSTM1 bridging NTRK1 and NGFR.
CC Forms a ternary complex with SQSTM1 and PRKCZ. Interacts with IL1RL1.
CC Interacts with AJUBA (By similarity). Interacts with TRAFD1. Interacts
CC with TICAM2. Interacts with ZFAND5. Interacts with ARRB1 and ARRB2 (By
CC similarity). Interacts with MAP3K7 and TAB1/MAP3K7IP1; during IL-1
CC signaling. Interacts with UBE2N. Interacts with TGFBR1, HDAC1 and
CC RANGAP1. Interacts with AKT1, AKT2 and AKT3. Interacts (via TRAF
CC domains) with NUMBL (via C-terminal) (By similarity). Interacts (via
CC TRAF domains) with DYNC2I2 (via WD domains). Interacts with RBCK1 (By
CC similarity). Interacts with LIMD1 (via LIM domains). Interacts with
CC RSAD2/viperin. Interacts with IFIT3 (via N-terminus) (By similarity).
CC Interacts (via C-terminus) with EIF2AK2/PKR (via the kinase catalytic
CC domain). Interacts with CARD14 (By similarity). Interacts with CD40 and
CC MAP3K8; the interaction is required for ERK activation. Interacts with
CC TICAM1 and this interaction is enhanced in the presence of WDFY1 (By
CC similarity). Interacts with TANK; this interaction increases in
CC response to DNA damage (By similarity). Interacts with USP10; this
CC interaction increases in response to DNA damage (By similarity).
CC Interacts with ZC3H12A; this interaction increases in response to DNA
CC damage and is stimulated by TANK (By similarity). Interacts with WDFY3
CC (PubMed:27330028). Interacts with TRIM13 (By similarity). Interacts
CC with GPS2 (PubMed:22424771). Interacts (via C-terminus) with SASH1 (By
CC similarity). Interacts with LRRC19 (By similarity). Interacts with
CC IL17RA AND TRAF3IP2. Interacts with TOMM70 (By similarity). Interacts
CC with AMBRA1; interaction is required to mediate 'Lys-63'-linked
CC ubiquitination of ULK1 (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 -!- 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.
CC {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).
CC {ECO:0000250|UniProtKB:Q9Y4K3, 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}.
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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; 108.
DR CORUM; P70196; -.
DR DIP; DIP-29812N; -.
DR IntAct; P70196; 42.
DR MINT; P70196; -.
DR STRING; 10090.ENSMUSP00000004949; -.
DR iPTMnet; P70196; -.
DR PhosphoSitePlus; P70196; -.
DR EPD; P70196; -.
DR MaxQB; P70196; -.
DR PaxDb; P70196; -.
DR PeptideAtlas; P70196; -.
DR PRIDE; P70196; -.
DR ProteomicsDB; 258843; -. [P70196-1]
DR ProteomicsDB; 258844; -. [P70196-2]
DR Antibodypedia; 3895; 556 antibodies from 45 providers.
DR DNASU; 22034; -.
DR Ensembl; ENSMUST00000004949; ENSMUSP00000004949; ENSMUSG00000027164. [P70196-1]
DR GeneID; 22034; -.
DR KEGG; mmu:22034; -.
DR UCSC; uc008lhl.2; mouse. [P70196-2]
DR UCSC; uc008lhm.2; mouse. [P70196-1]
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; WMQKNNQ; -.
DR OrthoDB; 918518at2759; -.
DR PhylomeDB; P70196; -.
DR TreeFam; TF321154; -.
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-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-975871; MyD88 cascade initiated on plasma membrane. [P70196-1]
DR UniPathway; UPA00143; -.
DR BioGRID-ORCS; 22034; 21 hits in 75 CRISPR screens.
DR ChiTaRS; Traf6; mouse.
DR PRO; PR:P70196; -.
DR Proteomes; UP000000589; Chromosome 2.
DR RNAct; P70196; protein.
DR Bgee; ENSMUSG00000027164; Expressed in ileal epithelium and 210 other tissues.
DR Genevisible; P70196; MM.
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; ISO:MGI.
DR GO; GO:0009898; C:cytoplasmic side of plasma membrane; IDA:BHF-UCL.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0005811; C:lipid droplet; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; ISO:MGI.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; ISO:MGI.
DR GO; GO:0005886; C:plasma membrane; ISO:MGI.
DR GO; GO:0032991; C:protein-containing complex; ISO:MGI.
DR GO; GO:0042826; F:histone deacetylase binding; ISO:MGI.
DR GO; GO:0042802; F:identical protein binding; ISO:MGI.
DR GO; GO:0031435; F:mitogen-activated protein kinase kinase kinase binding; ISO:MGI.
DR GO; GO:0043422; F:protein kinase B binding; ISO:MGI.
DR GO; GO:0019901; F:protein kinase binding; ISO:MGI.
DR GO; GO:0047485; F:protein N-terminus binding; ISO:MGI.
DR GO; GO:0031996; F:thioesterase binding; ISO:MGI.
DR GO; GO:0005164; F:tumor necrosis factor receptor binding; ISO:MGI.
DR GO; GO:0032813; F:tumor necrosis factor receptor superfamily binding; IBA:GO_Central.
DR GO; GO:0031624; F:ubiquitin conjugating enzyme binding; ISO:MGI.
DR GO; GO:0061630; F:ubiquitin protein ligase activity; IDA:MGI.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; ISO:MGI.
DR GO; GO:0004842; F:ubiquitin-protein transferase activity; IDA:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0007250; P:activation of NF-kappaB-inducing kinase activity; ISO:MGI.
DR GO; GO:0032147; P:activation of protein kinase activity; ISO:MGI.
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:0046849; P:bone remodeling; IMP:UniProtKB.
DR GO; GO:0045453; P:bone resorption; IMP:UniProtKB.
DR GO; GO:0048468; P:cell development; IMP:MGI.
DR GO; GO:0071345; P:cellular response to cytokine stimulus; ISO:MGI.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; IEA:UniProtKB-KW.
DR GO; GO:0071222; P:cellular response to lipopolysaccharide; ISO:MGI.
DR GO; GO:0019221; P:cytokine-mediated signaling pathway; ISO:MGI.
DR GO; GO:0007249; P:I-kappaB kinase/NF-kappaB signaling; IMP:UniProtKB.
DR GO; GO:0006955; P:immune response; IMP:MGI.
DR GO; GO:0001701; P:in utero embryonic development; IMP:MGI.
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:0007254; P:JNK cascade; ISO:MGI.
DR GO; GO:0043011; P:myeloid dendritic cell differentiation; IMP:MGI.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; ISO:MGI.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; ISO:MGI.
DR GO; GO:0001843; P:neural tube closure; IMP:UniProtKB.
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:0051091; P:positive regulation of DNA-binding transcription factor activity; ISO:MGI.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB signaling; 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:MGI.
DR GO; GO:0032755; P:positive regulation of interleukin-6 production; IMP:MGI.
DR GO; GO:0046330; P:positive regulation of JNK cascade; IBA:GO_Central.
DR GO; GO:0043507; P:positive regulation of JUN kinase activity; ISO:MGI.
DR GO; GO:1904996; P:positive regulation of leukocyte adhesion to vascular endothelial cell; ISO:MGI.
DR GO; GO:0031666; P:positive regulation of lipopolysaccharide-mediated signaling pathway; IMP:UniProtKB.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; IMP:UniProtKB.
DR GO; GO:1901224; P:positive regulation of NIK/NF-kappaB signaling; ISO:MGI.
DR GO; GO:0045672; P:positive regulation of osteoclast differentiation; ISO:MGI.
DR GO; GO:0048661; P:positive regulation of smooth muscle cell proliferation; ISO:MGI.
DR GO; GO:0002726; P:positive regulation of T cell cytokine production; ISO:MGI.
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:MGI.
DR GO; GO:2000679; P:positive regulation of transcription regulatory region DNA binding; ISO:MGI.
DR GO; GO:0051865; P:protein autoubiquitination; ISO:MGI.
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 I-kappaB kinase/NF-kappaB signaling; IBA:GO_Central.
DR GO; GO:0002637; P:regulation of immunoglobulin production; IDA:MGI.
DR GO; GO:0070555; P:response to interleukin-1; ISO:MGI.
DR GO; GO:0007165; P:signal transduction; IDA:MGI.
DR GO; GO:0050852; P:T cell receptor signaling pathway; ISO:MGI.
DR GO; GO:0042088; P:T-helper 1 type immune response; IMP:MGI.
DR GO; GO:0033209; P:tumor necrosis factor-mediated signaling pathway; IBA:GO_Central.
DR CDD; cd03776; MATH_TRAF6; 1.
DR Gene3D; 2.60.210.10; -; 1.
DR Gene3D; 3.30.40.10; -; 3.
DR InterPro; IPR002083; MATH/TRAF_dom.
DR InterPro; IPR043211; TNF_rcpt-assoc_TRAF.
DR InterPro; IPR012227; TNF_rcpt-assoc_TRAF_met.
DR InterPro; IPR008974; TRAF-like.
DR InterPro; IPR027139; TRAF6.
DR InterPro; IPR037309; TRAF6_MATH.
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; PTHR10131; 1.
DR PANTHER; PTHR10131:SF131; PTHR10131:SF131; 1.
DR Pfam; PF18048; TRAF6_Z2; 1.
DR Pfam; PF02176; zf-TRAF; 1.
DR PIRSF; PIRSF015614; TRAF; 1.
DR SMART; SM00061; MATH; 1.
DR SMART; SM00184; RING; 1.
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 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 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
