ID TRAF3_HUMAN Reviewed; 568 AA. AC Q13114; B7Z8C4; Q12990; Q13076; Q13947; Q6AZX1; Q9UNL1; DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot. DT 17-OCT-2006, sequence version 2. DT 27-MAR-2024, entry version 244. DE RecName: Full=TNF receptor-associated factor 3 {ECO:0000312|HGNC:HGNC:12033}; DE EC=2.3.2.27 {ECO:0000269|PubMed:25847972}; DE AltName: Full=CD40 receptor-associated factor 1 {ECO:0000303|PubMed:7533327}; DE Short=CRAF1 {ECO:0000303|PubMed:7533327}; DE AltName: Full=CD40-binding protein {ECO:0000303|PubMed:7527023}; DE Short=CD40BP {ECO:0000303|PubMed:7527023}; DE AltName: Full=LMP1-associated protein 1 {ECO:0000303|PubMed:7859281}; DE Short=LAP1 {ECO:0000303|PubMed:7859281}; DE AltName: Full=RING-type E3 ubiquitin transferase TRAF3 {ECO:0000305}; GN Name=TRAF3 {ECO:0000312|HGNC:HGNC:12033}; GN Synonyms=CAP-1 {ECO:0000312|HGNC:HGNC:12033}, CRAF1 GN {ECO:0000303|PubMed:7533327}, TRAFAMN {ECO:0000250|UniProtKB:Q60803}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND INTERACTION WITH TNFRSF5. RX PubMed=7527023; DOI=10.1016/s0021-9258(18)43772-6; RA Hu H.M., O'Rourke K., Boguski M.S., Dixit V.M.; RT "A novel RING finger protein interacts with the cytoplasmic domain of RT CD40."; RL J. Biol. Chem. 269:30069-30072(1994). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), CHARACTERIZATION, AND INTERACTION RP WITH EBV LMP1. RC TISSUE=Lymphoma; RX PubMed=7859281; DOI=10.1016/0092-8674(95)90489-1; RA Mosialos G., Birkenbach M., Yalamanchili R., VanArsdale T., Ware C., RA Kieff E.; RT "The Epstein-Barr virus transforming protein LMP1 engages signaling RT proteins for the tumor necrosis factor receptor family."; RL Cell 80:389-399(1995). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), INTERACTION WITH TNFRSF5, AND RP VARIANT THR-129. RC TISSUE=Fetal brain; RX PubMed=7530216; DOI=10.1016/0014-5793(94)01406-q; RA Sato T., Irie S., Reed J.C.; RT "A novel member of the TRAF family of putative signal transducing proteins RT binds to the cytosolic domain of CD40."; RL FEBS Lett. 358:113-118(1995). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), INTERACTION WITH TNFRSF5, AND RP VARIANT THR-129. RX PubMed=7533327; DOI=10.1126/science.7533327; RA Cheng G., Cleary A.M., Ye Z.S., Hong D.I., Lederman S., Baltimore D.; RT "Involvement of CRAF1, a relative of TRAF, in CD40 signaling."; RL Science 267:1494-1498(1995). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Fetal brain; RA Li W.B., Gruber C., Jessee J., Polayes D.; RT "Full-length cDNA libraries and normalization."; RL Submitted (FEB-2003) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Thymus; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=12508121; DOI=10.1038/nature01348; RA Heilig R., Eckenberg R., Petit J.-L., Fonknechten N., Da Silva C., RA Cattolico L., Levy M., Barbe V., De Berardinis V., Ureta-Vidal A., RA Pelletier E., Vico V., Anthouard V., Rowen L., Madan A., Qin S., Sun H., RA Du H., Pepin K., Artiguenave F., Robert C., Cruaud C., Bruels T., RA Jaillon O., Friedlander L., Samson G., Brottier P., Cure S., Segurens B., RA Aniere F., Samain S., Crespeau H., Abbasi N., Aiach N., Boscus D., RA Dickhoff R., Dors M., Dubois I., Friedman C., Gouyvenoux M., James R., RA Madan A., Mairey-Estrada B., Mangenot S., Martins N., Menard M., Oztas S., RA Ratcliffe A., Shaffer T., Trask B., Vacherie B., Bellemere C., Belser C., RA Besnard-Gonnet M., Bartol-Mavel D., Boutard M., Briez-Silla S., RA Combette S., Dufosse-Laurent V., Ferron C., Lechaplais C., Louesse C., RA Muselet D., Magdelenat G., Pateau E., Petit E., Sirvain-Trukniewicz P., RA Trybou A., Vega-Czarny N., Bataille E., Bluet E., Bordelais I., Dubois M., RA Dumont C., Guerin T., Haffray S., Hammadi R., Muanga J., Pellouin V., RA Robert D., Wunderle E., Gauguet G., Roy A., Sainte-Marthe L., Verdier J., RA Verdier-Discala C., Hillier L.W., Fulton L., McPherson J., Matsuda F., RA Wilson R., Scarpelli C., Gyapay G., Wincker P., Saurin W., Quetier F., RA Waterston R., Hood L., Weissenbach J.; RT "The DNA sequence and analysis of human chromosome 14."; RL Nature 421:601-607(2003). RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC 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 [9] RP NUCLEOTIDE SEQUENCE [MRNA] OF 536-568. RX PubMed=10199393; DOI=10.1016/s0161-5890(98)00099-6; RA van Eyndhoven W.G., Frank D., Kalachikov S., Cleary A.M., Hong D.I., RA Cho E., Nasr S., Perez A.J., Mackus W.J.M., Cayanis E., Wellington S., RA Fischer S.G., Warburton D., Lederman S.; RT "A single gene for human TRAF-3 at chromosome 14q32.3 encodes a variety of RT mRNA species by alternative polyadenylation, mRNA splicing and RT transcription initiation."; RL Mol. Immunol. 35:1189-1206(1998). RN [10] RP INTERACTION WITH LTBR. RX PubMed=8663299; DOI=10.1074/jbc.271.25.14661; RA Nakano H., Oshima H., Chung W., Williams-Abbott L., Ware C.F., Yagita H., RA Okumura K.; RT "TRAF5, an activator of NF-kappaB and putative signal transducer for the RT lymphotoxin-beta receptor."; RL J. Biol. Chem. 271:14661-14664(1996). RN [11] RP INTERACTION WITH TANK. RX PubMed=8710854; DOI=10.1073/pnas.93.16.8241; RA Rothe M., Xiong J., Shu H.-B., Williamson K., Goddard A., Goeddel D.V.; RT "I-TRAF is a novel TRAF-interacting protein that regulates TRAF-mediated RT signal transduction."; RL Proc. Natl. Acad. Sci. U.S.A. 93:8241-8246(1996). RN [12] RP INTERACTION WITH TNFRSF8. RX PubMed=9168896; DOI=10.1006/bbrc.1997.6509; RA Boucher L.-M., Marengere L.E., Lu Y., Thukral S., Mak T.W.; RT "Binding sites of cytoplasmic effectors TRAF1, 2, and 3 on CD30 and other RT members of the TNF receptor superfamily."; RL Biochem. Biophys. Res. Commun. 233:592-600(1997). RN [13] RP INTERACTION WITH TNFRSF14. RX PubMed=9162022; DOI=10.1074/jbc.272.22.14029; RA Marsters S.A., Ayres T.M., Skubatch M., Gray C.L., Rothe M., Ashkenazi A.; RT "Herpesvirus entry mediator, a member of the tumor necrosis factor receptor RT (TNFR) family, interacts with members of the TNFR-associated factor family RT and activates the transcription factors NF-kappaB and AP-1."; RL J. Biol. Chem. 272:14029-14032(1997). RN [14] RP INTERACTION WITH MAP3K14. RX PubMed=9275204; DOI=10.1073/pnas.94.18.9792; RA Song H.Y., Regnier C.H., Kirschning C.J., Goeddel D.V., Rothe M.; RT "Tumor necrosis factor (TNF)-mediated kinase cascades: bifurcation of RT nuclear factor-kappaB and c-jun N-terminal kinase (JNK/SAPK) pathways at RT TNF receptor-associated factor 2."; RL Proc. Natl. Acad. Sci. U.S.A. 94:9792-9796(1997). RN [15] RP INTERACTION WITH TNFRSF5 AND TRAF5. RX PubMed=9718306; DOI=10.1021/bi981067q; RA Pullen S.S., Miller H.G., Everdeen D.S., Dang T.T., Crute J.J., Kehry M.R.; RT "CD40-tumor necrosis factor receptor-associated factor (TRAF) interactions: RT regulation of CD40 signaling through multiple TRAF binding sites and TRAF RT hetero-oligomerization."; RL Biochemistry 37:11836-11845(1998). RN [16] RP INTERACTION WITH TNFRSF4. RX PubMed=9488716; DOI=10.1074/jbc.273.10.5808; RA Kawamata S., Hori T., Imura A., Takaori-Kondo A., Uchiyama T.; RT "Activation of OX40 signal transduction pathways leads to tumor necrosis RT factor receptor-associated factor (TRAF) 2- and TRAF5-mediated NF-kappaB RT activation."; RL J. Biol. Chem. 273:5808-5814(1998). RN [17] RP INTERACTION WITH TNFRSF11A. RX PubMed=9774460; DOI=10.1074/jbc.273.43.28355; RA Wong B.R., Josien R., Lee S.Y., Vologodskaia M., Steinman R.M., Choi Y.; RT "The TRAF family of signal transducers mediates NF-kappaB activation by the RT TRANCE receptor."; RL J. Biol. Chem. 273:28355-28359(1998). RN [18] RP INTERACTION WITH MAP3K5. RX PubMed=9774977; DOI=10.1016/s1097-2765(00)80283-x; RA Nishitoh H., Saitoh M., Mochida Y., Takeda K., Nakano H., Rothe M., RA Miyazono K., Ichijo H.; RT "ASK1 is essential for JNK/SAPK activation by TRAF2."; RL Mol. Cell 2:389-395(1998). RN [19] RP INTERACTION WITH TNFRSF4 AND TNFRSF9. RX PubMed=9418902; DOI=10.1128/mcb.18.1.558; RA Arch R.H., Thompson C.B.; RT "4-1BB and Ox40 are members of a tumor necrosis factor (TNF)-nerve growth RT factor receptor subfamily that bind TNF receptor-associated factors and RT activate nuclear factor kappaB."; RL Mol. Cell. Biol. 18:558-565(1998). RN [20] RP INTERACTION WITH TNFRSF18. RC TISSUE=T-cell; RX PubMed=10037686; DOI=10.1074/jbc.274.10.6056; RA Kwon B., Yu K.-Y., Ni J., Yu G.-L., Jang I.-K., Kim Y.-J., Xing L., Liu D., RA Wang S.-X., Kwon B.S.; RT "Identification of a novel activation-inducible protein of the tumor RT necrosis factor receptor superfamily and its ligand."; RL J. Biol. Chem. 274:6056-6061(1999). RN [21] RP INTERACTION WITH MAP3K5. RX PubMed=10523862; DOI=10.1038/sj.onc.1202975; RA Hoeflich K.P., Yeh W.C., Yao Z., Mak T.W., Woodgett J.R.; RT "Mediation of TNF receptor-associated factor effector functions by RT apoptosis signal-regulating kinase-1 (ASK1)."; RL Oncogene 18:5814-5820(1999). RN [22] RP INTERACTION WITH TNFRSF19. RX PubMed=10809768; DOI=10.1074/jbc.275.20.15336; RA Eby M.T., Jasmin A., Kumar A., Sharma K., Chaudhary P.M.; RT "TAJ, a novel member of the tumor necrosis factor receptor family, RT activates the c-Jun N-terminal kinase pathway and mediates caspase- RT independent cell death."; RL J. Biol. Chem. 275:15336-15342(2000). RN [23] RP INTERACTION WITH TTRAP. RX PubMed=10764746; DOI=10.1074/jbc.m000531200; RA Pype S., Declercq W., Ibrahimi A., Michiels C., Van Rietschoten J.G.I., RA Dewulf N., de Boer M., Vandenabeele P., Huylebroeck D., Remacle J.E.; RT "TTRAP, a novel protein that associates with CD40, tumor necrosis factor RT (TNF) receptor-75 and TNF receptor-associated factors (TRAFs), and that RT inhibits nuclear factor-kappa B activation."; RL J. Biol. Chem. 275:18586-18593(2000). RN [24] RP INTERACTION WITH TRAF3IP1. RX PubMed=10791955; DOI=10.1074/jbc.m001095200; RA Ling L., Goeddel D.V.; RT "MIP-T3, a novel protein linking tumor necrosis factor receptor-associated RT factor 3 to the microtubule network."; RL J. Biol. Chem. 275:23852-23860(2000). RN [25] RP INTERACTION WITH TNFRSF17. RX PubMed=10903733; DOI=10.4049/jimmunol.165.3.1322; RA Hatzoglou A., Roussel J., Bourgeade M.-F., Rogier E., Madry C., Inoue J., RA Devergne O., Tsapis A.; RT "TNF receptor family member BCMA (B cell maturation) associates with TNF RT receptor-associated factor (TRAF) 1, TRAF2, and TRAF3 and activates NF- RT kappa B, elk-1, c-Jun N-terminal kinase, and p38 mitogen-activated protein RT kinase."; RL J. Immunol. 165:1322-1330(2000). RN [26] RP INTERACTION WITH EDAR. RX PubMed=11035039; DOI=10.1074/jbc.m008356200; RA Kumar A., Eby M.T., Sinha S., Jasmin A., Chaudhary P.M.; RT "The ectodermal dysplasia receptor activates the nuclear factor-kappaB, RT JNK, and cell death pathways and binds to ectodysplasin A."; RL J. Biol. Chem. 276:2668-2677(2001). RN [27] RP FUNCTION, SUBCELLULAR LOCATION, AND SUBUNIT. RX PubMed=15383523; DOI=10.1074/jbc.m407284200; RA He L., Grammer A.C., Wu X., Lipsky P.E.; RT "TRAF3 forms heterotrimers with TRAF2 and modulates its ability to mediate RT NF-{kappa}B activation."; RL J. Biol. Chem. 279:55855-55865(2004). RN [28] RP FUNCTION, PROTEASOMAL DEGRADATION, AND INTERACTION WITH MAP3K14. RX PubMed=15084608; DOI=10.1074/jbc.m403286200; RA Liao G., Zhang M., Harhaj E.W., Sun S.C.; RT "Regulation of the NF-kappaB-inducing kinase by tumor necrosis factor RT receptor-associated factor 3-induced degradation."; RL J. Biol. Chem. 279:26243-26250(2004). RN [29] RP INTERACTION WITH OTUD5 AND TBK1, FUNCTION AS E3 PROTEIN-UBIQUITIN LIGASE, RP AND UBIQUITINATION. RX PubMed=17991829; DOI=10.1126/science.1145918; RA Kayagaki N., Phung Q., Chan S., Chaudhari R., Quan C., O'Rourke K.M., RA Eby M., Pietras E., Cheng G., Bazan J.F., Zhang Z., Arnott D., Dixit V.M.; RT "DUBA: a deubiquitinase that regulates type I interferon production."; RL Science 318:1628-1632(2007). RN [30] RP INTERACTION WITH NEW YORK HANTAVIRUS GLYCOPROTEIN N (MICROBIAL INFECTION). RX PubMed=18614628; DOI=10.1128/jvi.00290-08; RA Alff P.J., Sen N., Gorbunova E., Gavrilovskaya I.N., Mackow E.R.; RT "The NY-1 hantavirus Gn cytoplasmic tail coprecipitates TRAF3 and inhibits RT cellular interferon responses by disrupting TBK1-TRAF3 complex formation."; RL J. Virol. 82:9115-9122(2008). RN [31] RP INTERACTION WITH SRC. RX PubMed=19419966; DOI=10.1074/jbc.m808233200; RA Johnsen I.B., Nguyen T.T., Bergstroem B., Fitzgerald K.A., Anthonsen M.W.; RT "The tyrosine kinase c-Src enhances RIG-I (retinoic acid-inducible gene I)- RT elicited antiviral signaling."; RL J. Biol. Chem. 284:19122-19131(2009). RN [32] RP UBIQUITINATION, MUTAGENESIS OF TYR-441 AND GLN-443, AND INTERACTION WITH RP RNF216 AND MAVS. RX PubMed=19893624; DOI=10.1371/journal.ppat.1000650; RA Nakhaei P., Mesplede T., Solis M., Sun Q., Zhao T., Yang L., Chuang T.H., RA Ware C.F., Lin R., Hiscott J.; RT "The E3 ubiquitin ligase Triad3A negatively regulates the RIG-I/MAVS RT signaling pathway by targeting TRAF3 for degradation."; RL PLoS Pathog. 5:E1000650-E1000650(2009). RN [33] RP UBIQUITINATION, AND INTERACTION WITH OTUB1 AND OTUB2. RX PubMed=19996094; DOI=10.1074/jbc.m109.074971; RA Li S., Zheng H., Mao A.P., Zhong B., Li Y., Liu Y., Gao Y., Ran Y., RA Tien P., Shu H.B.; RT "Regulation of virus-triggered signaling by OTUB1- and OTUB2-mediated RT deubiquitination of TRAF3 and TRAF6."; RL J. Biol. Chem. 285:4291-4297(2010). RN [34] RP FUNCTION, INTERACTION WITH BIRC2 AND BIRC3, SUBCELLULAR LOCATION, AND RP UBIQUITINATION. RX PubMed=20097753; DOI=10.1074/jbc.m109.071043; RA Mao A.P., Li S., Zhong B., Li Y., Yan J., Li Q., Teng C., Shu H.B.; RT "Virus-triggered ubiquitination of TRAF3/6 by cIAP1/2 is essential for RT induction of interferon-beta (IFN-beta) and cellular antiviral response."; RL J. Biol. Chem. 285:9470-9476(2010). RN [35] RP FUNCTION. RX PubMed=20185819; DOI=10.1074/jbc.m109.076091; RA Bista P., Zeng W., Ryan S., Bailly V., Browning J.L., Lukashev M.E.; RT "TRAF3 controls activation of the canonical and alternative NFkappaB by the RT lymphotoxin beta receptor."; RL J. Biol. Chem. 285:12971-12978(2010). RN [36] RP UBIQUITINATION, AND FUNCTION. RX PubMed=19937093; DOI=10.1007/s11010-009-0315-y; RA Li S., Lu K., Wang J., An L., Yang G., Chen H., Cui Y., Yin X., Xie P., RA Xing G., He F., Zhang L.; RT "Ubiquitin ligase Smurf1 targets TRAF family proteins for ubiquitination RT and degradation."; RL Mol. Cell. Biochem. 338:11-17(2010). RN [37] RP INTERACTION WITH OPTN AND TBK1. RX PubMed=20174559; DOI=10.1371/journal.ppat.1000778; RA Mankouri J., Fragkoudis R., Richards K.H., Wetherill L.F., Harris M., RA Kohl A., Elliott R.M., Macdonald A.; RT "Optineurin negatively regulates the induction of IFNbeta in response to RT RNA virus infection."; RL PLoS Pathog. 6:E1000778-E1000778(2010). RN [38] RP INTERACTION WITH CARD14. RX PubMed=21302310; DOI=10.1002/jcp.22667; RA Scudiero I., Zotti T., Ferravante A., Vessichelli M., Vito P., Stilo R.; RT "Alternative splicing of CARMA2/CARD14 transcripts generates protein RT variants with differential effect on NF-kappaB activation and endoplasmic RT reticulum stress-induced cell death."; RL J. Cell. Physiol. 226:3121-3131(2011). RN [39] RP INTERACTION WITH PTPN22. RX PubMed=23871208; DOI=10.1016/j.immuni.2013.06.013; RA Wang Y., Shaked I., Stanford S.M., Zhou W., Curtsinger J.M., Mikulski Z., RA Shaheen Z.R., Cheng G., Sawatzke K., Campbell A.M., Auger J.L., Bilgic H., RA Shoyama F.M., Schmeling D.O., Balfour H.H. Jr., Hasegawa K., Chan A.C., RA Corbett J.A., Binstadt B.A., Mescher M.F., Ley K., Bottini N., RA Peterson E.J.; RT "The autoimmunity-associated gene PTPN22 potentiates toll-like receptor- RT driven, type 1 interferon-dependent immunity."; RL Immunity 39:111-122(2013). RN [40] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-9, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [41] RP INTERACTION WITH NEW YORK HANTAVIRUS GLYCOPROTEIN N (MICROBIAL INFECTION), RP INTERACTION WITH ANDES HANTAVIRUS GLYCOPROTEIN N (MICROBIAL INFECTION), AND RP INTERACTION WITH TULA HANTAVIRUS GLYCOPROTEIN N (MICROBIAL INFECTION). RX PubMed=24390324; DOI=10.1128/jvi.02647-13; RA Matthys V.S., Cimica V., Dalrymple N.A., Glennon N.B., Bianco C., RA Mackow E.R.; RT "Hantavirus GnT elements mediate TRAF3 binding and inhibit RIG-I/TBK1- RT directed beta interferon transcription by blocking IRF3 phosphorylation."; RL J. Virol. 88:2246-2259(2014). RN [42] RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, AND MUTAGENESIS OF RP CYS-68 AND HIS-70. RX PubMed=25847972; DOI=10.4049/jimmunol.1402851; RA Guan K., Wei C., Zheng Z., Song T., Wu F., Zhang Y., Cao Y., Ma S., RA Chen W., Xu Q., Xia W., Gu J., He X., Zhong H.; RT "MAVS Promotes Inflammasome Activation by Targeting ASC for K63-Linked RT Ubiquitination via the E3 Ligase TRAF3."; RL J. Immunol. 194:4880-4890(2015). RN [43] RP INTERACTION WITH GAPDH. RX PubMed=27387501; DOI=10.1074/jbc.m116.738278; RA Gao X., Pham T.H., Feuerbacher L.A., Chen K., Hays M.P., Singh G., RA Rueter C., Hurtado-Guerrero R., Hardwidge P.R.; RT "Citrobacter rodentium NleB protein inhibits tumor necrosis factor (TNF) RT receptor-associated factor 3 (TRAF3) ubiquitination to reduce host type I RT interferon production."; RL J. Biol. Chem. 291:18232-18238(2016). RN [44] RP FUNCTION, UBIQUITINATION AT LYS-168, MUTAGENESIS OF LYS-168, AND RP INTERACTION WITH RALGDS. RX PubMed=27438768; DOI=10.1016/j.immuni.2016.06.023; RA Miao Y., Wu J., Abraham S.N.; RT "Ubiquitination of Innate Immune Regulator TRAF3 Orchestrates Expulsion of RT Intracellular Bacteria by Exocyst Complex."; RL Immunity 45:94-105(2016). RN [45] RP INTERACTION WITH DDX3X; IKBKE; IRF3 AND MAVS, UBIQUITINATION, AND RP MUTAGENESIS OF 68-CYS--HIS-70. RX PubMed=27980081; DOI=10.1042/bcj20160956; RA Gu L., Fullam A., McCormack N., Hoehn Y., Schroeder M.; RT "DDX3 directly regulates TRAF3 ubiquitination and acts as a scaffold to co- RT ordinate assembly of signalling complexes downstream from MAVS."; RL Biochem. J. 474:571-587(2017). RN [46] RP FUNCTION, INTERACTION WITH TRIM35, SUBCELLULAR LOCATION, AND RP UBIQUITINATION. RX PubMed=32562145; DOI=10.1007/s13238-020-00734-6; RA Sun N., Jiang L., Ye M., Wang Y., Wang G., Wan X., Zhao Y., Wen X., RA Liang L., Ma S., Liu L., Bu Z., Chen H., Li C.; RT "TRIM35 mediates protection against influenza infection by activating TRAF3 RT and degrading viral PB2."; RL Protein Cell 11:894-914(2020). RN [47] RP FUNCTION, CLEAVAGE BY ENTEROVIRUS D68 PROTEASE 2A (MICROBIAL INFECTION), RP AND MUTAGENESIS OF GLY-462. RX PubMed=33148796; DOI=10.1128/jvi.01856-20; RA Kang J., Pang Z., Zhou Z., Li X., Liu S., Cheng J., Liu P., Tan W., RA Wang Z., Wang T.; RT "Enterovirus D68 Protease 2Apro Targets TRAF3 To Subvert Host Innate Immune RT Responses."; RL J. Virol. 95:0-0(2021). RN [48] RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH ATP1B1, AND RP UBIQUITINATION. RX PubMed=34011520; DOI=10.4049/jimmunol.2001262; RA Cao W., Guo Y., Cheng Z., Xu G., Zuo Q., Nie L., Huang Y., Liu S., Zhu Y.; RT "Inducible ATP1B1 Upregulates Antiviral Innate Immune Responses by the RT Ubiquitination of TRAF3 and TRAF6."; RL J. Immunol. 206:2668-2681(2021). RN [49] RP FUNCTION, UBIQUITINATION AT CYS-56 AND CYS-124 BY NEDD4L, AND MUTAGENESIS RP OF CYS-56 AND CYS-124. RX PubMed=33608556; DOI=10.1038/s41467-021-21456-1; RA Gao P., Ma X., Yuan M., Yi Y., Liu G., Wen M., Jiang W., Ji R., Zhu L., RA Tang Z., Yu Q., Xu J., Yang R., Xia S., Yang M., Pan J., Yuan H., An H.; RT "E3 ligase Nedd4l promotes antiviral innate immunity by catalyzing K29- RT linked cysteine ubiquitination of TRAF3."; RL Nat. Commun. 12:1194-1194(2021). RN [50] RP INTERACTION WITH FBXO11, AND UBIQUITINATION. RX PubMed=36897010; DOI=10.1002/jmv.28655; RA Gao L., Gao Y., Han K., Wang Z., Meng F., Liu J., Zhao X., Shao Y., RA Shen J., Sun W., Liu Y., Xu H., Du X., Li J., Qin F.X.; RT "FBXO11 amplifies type I interferon signaling to exert antiviral effects by RT facilitating the assemble of TRAF3-TBK1-IRF3 complex."; RL J. Med. Virol. 95:e28655-e28655(2023). RN [51] RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 341-568, AND X-RAY CRYSTALLOGRAPHY RP (3.5 ANGSTROMS) OF 341-568 IN COMPLEX WITH TNFRSF5. RX PubMed=10984535; DOI=10.1073/pnas.97.19.10395; RA Ni C.Z., Welsh K., Leo E., Chiou C.K., Wu H., Reed J.C., Ely K.R.; RT "Molecular basis for CD40 signaling mediated by TRAF3."; RL Proc. Natl. Acad. Sci. U.S.A. 97:10395-10399(2000). RN [52] RP X-RAY CRYSTALLOGRAPHY (3.5 ANGSTROMS) OF 377-568 IN COMPLEX WITH TANK, AND RP X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS) OF 377-568 IN COMPLEX WITH TNFRSF5. RX PubMed=12005438; DOI=10.1016/s0969-2126(02)00733-5; RA Li C., Ni C.Z., Havert M.L., Cabezas E., He J., Kaiser D., Reed J.C., RA Satterthwait A.C., Cheng G., Ely K.R.; RT "Downstream regulator TANK binds to the CD40 recognition site on TRAF3."; RL Structure 10:403-411(2002). RN [53] RP X-RAY CRYSTALLOGRAPHY (3.5 ANGSTROMS) OF 377-568 IN COMPLEX WITH LTBR, RP MUTAGENESIS OF TYR-459; PHE-512 AND PHE-521, INTERACTION WITH TANK AND RP CD40, AND SUBUNIT. RX PubMed=14517219; DOI=10.1074/jbc.m309381200; RA Li C., Norris P.S., Ni C.Z., Havert M.L., Chiong E.M., Tran B.R., RA Cabezas E., Reed J.C., Satterthwait A.C., Ware C.F., Ely K.R.; RT "Structurally distinct recognition motifs in lymphotoxin-beta receptor and RT CD40 for tumor necrosis factor receptor-associated factor (TRAF)-mediated RT signaling."; RL J. Biol. Chem. 278:50523-50529(2003). RN [54] RP X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF 377-568 IN COMPLEX WITH TNFRSF13C RP PEPTIDE, SUBUNIT, AND INTERACTION WITH TNFRSF13C. RX PubMed=15585864; DOI=10.4049/jimmunol.173.12.7394; RA Ni C.Z., Oganesyan G., Welsh K., Zhu X., Reed J.C., Satterthwait A.C., RA Cheng G., Ely K.R.; RT "Key molecular contacts promote recognition of the BAFF receptor by TNF RT receptor-associated factor 3: implications for intracellular signaling RT regulation."; RL J. Immunol. 173:7394-7400(2004). RN [55] RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 377-568 IN COMPLEX WITH RP EPSTEIN-BARR VIRUS PROTEIN LMP1 (MICROBIAL INFECTION), AND SUBUNIT. RX PubMed=16009714; DOI=10.1074/jbc.m502511200; RA Wu S., Xie P., Welsh K., Li C., Ni C.Z., Zhu X., Reed J.C., RA Satterthwait A.C., Bishop G.A., Ely K.R.; RT "LMP1 protein from the Epstein-Barr virus is a structural CD40 decoy in B RT lymphocytes for binding to TRAF3."; RL J. Biol. Chem. 280:33620-33626(2005). RN [56] RP STRUCTURE BY NMR OF 43-101. RG RIKEN structural genomics initiative (RSGI); RT "Solution structure of the zinc finger, C3HC4 type (RING finger) domain of RT TNF receptor-associated factor 3."; RL Submitted (FEB-2008) to the PDB data bank. RN [57] RP VARIANT IIAE5 TRP-118. RX PubMed=20832341; DOI=10.1016/j.immuni.2010.08.014; RA Perez de Diego R., Sancho-Shimizu V., Lorenzo L., Puel A., Plancoulaine S., RA Picard C., Herman M., Cardon A., Durandy A., Bustamante J., RA Vallabhapurapu S., Bravo J., Warnatz K., Chaix Y., Cascarrigny F., RA Lebon P., Rozenberg F., Karin M., Tardieu M., Al-Muhsen S., Jouanguy E., RA Zhang S.Y., Abel L., Casanova J.L.; RT "Human TRAF3 adaptor molecule deficiency leads to impaired Toll-like RT receptor 3 response and susceptibility to herpes simplex encephalitis."; RL Immunity 33:400-411(2010). CC -!- FUNCTION: Cytoplasmic E3 ubiquitin ligase that regulates various CC signaling pathways, such as the NF-kappa-B, mitogen-activated protein CC kinase (MAPK) and interferon regulatory factor (IRF) pathways, and thus CC controls a lot of biological processes in both immune and non-immune CC cell types (PubMed:33148796, PubMed:33608556). In TLR and RLR signaling CC pathways, acts as an E3 ubiquitin ligase promoting the synthesis of CC 'Lys-63'-linked polyubiquitin chains on several substrates such as ASC CC that lead to the activation of the type I interferon response or the CC inflammasome (PubMed:25847972, PubMed:27980081). Following the CC activation of certain TLRs such as TLR4, acts as a negative NF-kappa-B CC regulator, possibly to avoid unregulated inflammatory response, and its CC degradation via 'Lys-48'-linked polyubiquitination is required for MAPK CC activation and production of inflammatory cytokines. Alternatively, CC when TLR4 orchestrates bacterial expulsion, TRAF3 undergoes 'Lys-33'- CC linked polyubiquitination and subsequently binds to RALGDS, mobilizing CC the exocyst complex to rapidly expel intracellular bacteria back for CC clearance (PubMed:27438768). Acts also as a constitutive negative CC regulator of the alternative NF-kappa-B pathway, which controls B-cell CC survival and lymphoid organ development. Required for normal antibody CC isotype switching from IgM to IgG. Plays a role T-cell dependent immune CC responses. Down-regulates proteolytic processing of NFKB2, and thereby CC inhibits non-canonical activation of NF-kappa-B. Promotes CC ubiquitination and proteasomal degradation of MAP3K14. CC {ECO:0000269|PubMed:15084608, ECO:0000269|PubMed:15383523, CC ECO:0000269|PubMed:17991829, ECO:0000269|PubMed:19937093, CC ECO:0000269|PubMed:20097753, ECO:0000269|PubMed:20185819, CC ECO:0000269|PubMed:25847972, ECO:0000269|PubMed:27980081, CC ECO:0000269|PubMed:32562145, ECO:0000269|PubMed:33148796, CC ECO:0000269|PubMed:33608556, ECO:0000269|PubMed:34011520}. 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:0000269|PubMed:25847972}; CC -!- SUBUNIT: Homotrimer. Heterotrimer with TRAF2 and TRAF5. Interacts with CC LTBR/TNFRSF3, TNFRSF4, TNFRSF5/CD40, TNFRSF8/CD30, TNFRSF13C CC TNFRSF17/BCMA, TLR4 and EDAR. Interacts with MAP3K5, MAP3K14, CC TRAIP/TRIP, TDP2/TTRAP, TANK/ITRAF and TRAF3IP1. Interaction with CC TNFRSF5/CD40 is modulated by TANK/ITRAF, which competes for the same CC binding site. Interacts with TICAM1. Interacts with TRAFD1. Interacts CC with OTUB1, OTUB2 and OTUD5. Interacts with RNF216, OPTN and TBK1. CC Identified in a complex with TRAF2, MAP3K14 and BIRC3. Interacts with CC BIRC2 and BIRC3. Upon exposure to bacterial lipopolysaccharide (LPS), CC recruited to a transient complex containing TLR4, TRAF3, TRAF6, IKBKG, CC MAP3K7, MYD88, TICAM1, BIRC2, BIRC3 and UBE2N (By similarity). CC Interacts (via RING-type zinc finger domain) with SRC. Interacts with CC CARD14. Interacts (via MATH domain) with PTPN22; the interaction CC promotes TRAF3 polyubiquitination (PubMed:23871208). Interacts with CC MAVS (PubMed:19893624, PubMed:27980081). Directly interacts with DDX3X; CC this interaction stimulates TRAF3 'Lys-63' ubiquitination CC (PubMed:27980081). Interacts with IRF3 (PubMed:27980081). Interacts CC with IKBKE in the course of Sendai virus infection (PubMed:27980081). CC Interacts with TRIM35 (PubMed:32562145). Interacts with GAPDH; CC promoting TRAF3 ubiquitination (PubMed:27387501). Interacts with PPP3CA CC and PPP3CB (By similarity). Interacts with ATP1B1; promoting TRAF3 CC ubiquitination (PubMed:27387501). Interacts with RALGDS CC (PubMed:27438768). Interacts with FBXO11 (PubMed:36897010). CC {ECO:0000250|UniProtKB:Q60803, ECO:0000269|PubMed:10037686, CC ECO:0000269|PubMed:10523862, ECO:0000269|PubMed:10764746, CC ECO:0000269|PubMed:10791955, ECO:0000269|PubMed:10809768, CC ECO:0000269|PubMed:10903733, ECO:0000269|PubMed:10984535, CC ECO:0000269|PubMed:11035039, ECO:0000269|PubMed:12005438, CC ECO:0000269|PubMed:14517219, ECO:0000269|PubMed:15084608, CC ECO:0000269|PubMed:15383523, ECO:0000269|PubMed:15585864, CC ECO:0000269|PubMed:16009714, ECO:0000269|PubMed:17991829, CC ECO:0000269|PubMed:19419966, ECO:0000269|PubMed:19893624, CC ECO:0000269|PubMed:19996094, ECO:0000269|PubMed:20097753, CC ECO:0000269|PubMed:20174559, ECO:0000269|PubMed:21302310, CC ECO:0000269|PubMed:23871208, ECO:0000269|PubMed:27387501, CC ECO:0000269|PubMed:27438768, ECO:0000269|PubMed:27980081, CC ECO:0000269|PubMed:32562145, ECO:0000269|PubMed:36897010, CC ECO:0000269|PubMed:7527023, ECO:0000269|PubMed:7530216, CC ECO:0000269|PubMed:7533327, ECO:0000269|PubMed:8663299, CC ECO:0000269|PubMed:8710854, ECO:0000269|PubMed:9162022, CC ECO:0000269|PubMed:9168896, ECO:0000269|PubMed:9275204, CC ECO:0000269|PubMed:9418902, ECO:0000269|PubMed:9488716, CC ECO:0000269|PubMed:9718306, ECO:0000269|PubMed:9774460, CC ECO:0000269|PubMed:9774977}. CC -!- SUBUNIT: (Microbial infection) Interacts (via N-terminus) with New York CC hantavirus glycoprotein N (via C-terminus); this interaction inhibits CC the formation of TRAF3-TBK1 complexes. {ECO:0000269|PubMed:18614628, CC ECO:0000269|PubMed:24390324}. CC -!- SUBUNIT: (Microbial infection) Interacts with Andes hantavirus CC glycoprotein N (via C-terminus); this interaction inhibits the CC formation of TRAF3-TBK1 complexes. {ECO:0000269|PubMed:24390324}. CC -!- SUBUNIT: (Microbial infection) Interacts with Tula hantavirus CC glycoprotein N (via C-terminus); this interaction inhibits the CC formation of TRAF3-TBK1 complexes. {ECO:0000269|PubMed:24390324}. CC -!- SUBUNIT: (Microbial infection) Interacts with Epstein-Barr virus CC protein LMP1. {ECO:0000269|PubMed:7859281}. CC -!- INTERACTION: CC Q13114; Q8N9N2-2: ASCC1; NbExp=3; IntAct=EBI-357631, EBI-10962548; CC Q13114; Q86UB2: BIVM; NbExp=6; IntAct=EBI-357631, EBI-12191873; CC Q13114; P15056: BRAF; NbExp=2; IntAct=EBI-357631, EBI-365980; CC Q13114; Q5T681: C10orf62; NbExp=3; IntAct=EBI-357631, EBI-744052; CC Q13114; Q8IYE1: CCDC13; NbExp=3; IntAct=EBI-357631, EBI-10961312; CC Q13114; Q52MB2: CCDC184; NbExp=3; IntAct=EBI-357631, EBI-10179526; CC Q13114; P25942: CD40; NbExp=3; IntAct=EBI-357631, EBI-525714; CC Q13114; Q16543: CDC37; NbExp=3; IntAct=EBI-357631, EBI-295634; CC Q13114; Q9HAV5: EDA2R; NbExp=2; IntAct=EBI-357631, EBI-526033; CC Q13114; Q9Y692: GMEB1; NbExp=2; IntAct=EBI-357631, EBI-2339665; CC Q13114; Q9UKD1: GMEB2; NbExp=3; IntAct=EBI-357631, EBI-948296; CC Q13114; Q9Y547: IFT25; NbExp=3; IntAct=EBI-357631, EBI-747101; CC Q13114; Q96PC2: IP6K3; NbExp=5; IntAct=EBI-357631, EBI-10990676; CC Q13114; Q8TBB1: LNX1; NbExp=3; IntAct=EBI-357631, EBI-739832; CC Q13114; P36941: LTBR; NbExp=2; IntAct=EBI-357631, EBI-3509981; CC Q13114; Q99558: MAP3K14; NbExp=8; IntAct=EBI-357631, EBI-358011; CC Q13114; Q96HA8: NTAQ1; NbExp=3; IntAct=EBI-357631, EBI-741158; CC Q13114; Q17RL8: PDZD4; NbExp=3; IntAct=EBI-357631, EBI-10239064; CC Q13114; O75928-2: PIAS2; NbExp=3; IntAct=EBI-357631, EBI-348567; CC Q13114; Q96HA1-2: POM121; NbExp=3; IntAct=EBI-357631, EBI-11956563; CC Q13114; P28062-2: PSMB8; NbExp=3; IntAct=EBI-357631, EBI-372312; CC Q13114; Q9Y2R2: PTPN22; NbExp=2; IntAct=EBI-357631, EBI-1211241; CC Q13114; P54725: RAD23A; NbExp=3; IntAct=EBI-357631, EBI-746453; CC Q13114; Q13546: RIPK1; NbExp=3; IntAct=EBI-357631, EBI-358507; CC Q13114; O43353: RIPK2; NbExp=6; IntAct=EBI-357631, EBI-358522; CC Q13114; Q0D2K3: RIPPLY1; NbExp=3; IntAct=EBI-357631, EBI-10226430; CC Q13114; P78317: RNF4; NbExp=3; IntAct=EBI-357631, EBI-2340927; CC Q13114; O95721: SNAP29; NbExp=4; IntAct=EBI-357631, EBI-490676; CC Q13114; Q92844: TANK; NbExp=7; IntAct=EBI-357631, EBI-356349; CC Q13114; Q9UHD2: TBK1; NbExp=4; IntAct=EBI-357631, EBI-356402; CC Q13114; Q13114: TRAF3; NbExp=5; IntAct=EBI-357631, EBI-357631; CC Q13114; Q8TDR0: TRAF3IP1; NbExp=8; IntAct=EBI-357631, EBI-928811; CC Q13114; O00463: TRAF5; NbExp=4; IntAct=EBI-357631, EBI-523498; CC Q13114; Q7KZS0: UBE2I; NbExp=3; IntAct=EBI-357631, EBI-10180829; CC Q13114; P61964: WDR5; NbExp=2; IntAct=EBI-357631, EBI-540834; CC Q13114; Q6ZSB9: ZBTB49; NbExp=3; IntAct=EBI-357631, EBI-2859943; CC Q13114; Q15326: ZMYND11; NbExp=2; IntAct=EBI-357631, EBI-2623509; CC Q13114; Q8NAM6: ZSCAN4; NbExp=3; IntAct=EBI-357631, EBI-7252920; CC Q13114; Q9QYP6: Azi2; Xeno; NbExp=2; IntAct=EBI-357631, EBI-6115874; CC Q13114; P15314: Irf1; Xeno; NbExp=2; IntAct=EBI-357631, EBI-6115486; CC Q13114; A2APF7: Zbp1; Xeno; NbExp=2; IntAct=EBI-357631, EBI-6115394; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:25847972, CC ECO:0000269|PubMed:34011520}. Endosome {ECO:0000250|UniProtKB:Q60803}. CC Mitochondrion {ECO:0000269|PubMed:32562145}. Note=Undergoes endocytosis CC together with TLR4 upon LPS signaling (By similarity). Co-localized to CC mitochondria with TRIM35 (PubMed:32562145). CC {ECO:0000250|UniProtKB:Q60803, ECO:0000269|PubMed:32562145}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q13114-1; Sequence=Displayed; CC Name=2; CC IsoId=Q13114-2; Sequence=VSP_040040; CC -!- DOMAIN: The MATH/TRAF domain binds to receptor cytoplasmic domains. CC -!- DOMAIN: The Ring-type zinc finger domain is required for its function CC in down-regulation of NFKB2 proteolytic processing. CC {ECO:0000250|UniProtKB:Q60803}. CC -!- PTM: Undergoes 'Lys-48'-linked polyubiquitination, leading to its CC proteasomal degradation in response to signaling by TNFSF13B, TLR4 or CC through CD40. 'Lys-48'-linked polyubiquitinated form is deubiquitinated CC by OTUD7B, preventing TRAF3 proteolysis and over-activation of non- CC canonical NF-kappa-B. Undergoes 'Lys-63'-linked ubiquitination during CC early stages of virus infection, and 'Lys-48'-linked ubiquitination CC during later stages. Undergoes both 'Lys-48'-linked and 'Lys-63'-linked CC ubiquitination in response to TLR3 and TLR4 signaling. 'Lys-63'-linked CC ubiquitination can be mediated by TRIM35. Deubiquitinated by OTUB1, CC OTUB2 and OTUD5. Undergoes 'Lys-63'-linked deubiquitination by MYSM1 to CC terminate the pattern-recognition receptors/PRRs pathways (By CC similarity). Undergoes also 'Lys-29'-linked ubiquitination on Cys-56 CC and Cys-124 by NEDD4L; leading to increased 'Lys-48'- and 'Lys-63'- CC linked ubiquitination as well as increased binding to TBK1 CC (PubMed:33608556). TLR4 signals emanating from bacteria containing CC vesicles trigger 'Lys-33'-linked polyubiquitination that promotes the CC assembly of the exocyst complex thereby connecting innate immune CC signaling to the cellular trafficking apparatus (PubMed:27438768). CC Deubiquitinated by USP25 during viral infection, leading to TRAF3 CC stabilization and type I interferon production (By similarity). CC Ubiquitinated at Lys-329 by the SCF(FBXL2) complex, leading to its CC degradation by the proteasome (By similarity). 'Lys-63'-linked CC ubiquitination by FBXO11 in a NEDD8-dependent manner promotes the CC amplification of IFN-I signaling (PubMed:36897010). CC {ECO:0000250|UniProtKB:Q60803, ECO:0000269|PubMed:17991829, CC ECO:0000269|PubMed:19893624, ECO:0000269|PubMed:19937093, CC ECO:0000269|PubMed:19996094, ECO:0000269|PubMed:20097753, CC ECO:0000269|PubMed:27438768, ECO:0000269|PubMed:27980081, CC ECO:0000269|PubMed:32562145, ECO:0000269|PubMed:33608556, CC ECO:0000269|PubMed:34011520, ECO:0000269|PubMed:36897010}. CC -!- PTM: (Microbial infection) Cleaved by enterovirus D68 protease 2A; CC leading to inhibition of NF-kappa-B or IFN-beta triggered by TRAF3. CC {ECO:0000269|PubMed:33148796}. CC -!- DISEASE: Encephalopathy, acute, infection-induced, 5, herpes-specific CC (IIAE5) [MIM:614849]: A rare complication of human herpesvirus 1 (HHV- CC 1) infection, occurring in only a small minority of HHV-1 infected CC individuals. It is characterized by hemorrhagic necrosis of parts of CC the temporal and frontal lobes. Onset is over several days and involves CC fever, headache, seizures, stupor, and often coma, frequently with a CC fatal outcome. {ECO:0000269|PubMed:20832341}. Note=Disease CC susceptibility is associated with variants affecting the gene CC represented in this entry. CC -!- SIMILARITY: Belongs to the TNF receptor-associated factor family. A CC subfamily. {ECO:0000305}. CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/271/TRAF3"; 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; U15637; AAA56753.1; -; mRNA. DR EMBL; U19260; AAA65732.1; -; mRNA. DR EMBL; L38509; AAA68195.1; -; mRNA. DR EMBL; U21092; AAC50112.1; -; mRNA. DR EMBL; BX247977; CAD62311.1; -; mRNA. DR EMBL; AK303172; BAH13910.1; -; mRNA. DR EMBL; AL117209; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC075087; AAH75087.1; -; mRNA. DR EMBL; BC075086; AAH75086.1; -; mRNA. DR EMBL; AF110908; AAD29276.1; -; mRNA. DR CCDS; CCDS55946.1; -. [Q13114-2] DR CCDS; CCDS9975.1; -. [Q13114-1] DR PIR; A55960; A55960. DR PIR; S68467; S68467. DR RefSeq; NP_001186356.1; NM_001199427.1. [Q13114-2] DR RefSeq; NP_003291.2; NM_003300.3. [Q13114-1] DR RefSeq; NP_663777.1; NM_145725.2. [Q13114-1] DR RefSeq; NP_663778.1; NM_145726.2. DR RefSeq; XP_011535420.1; XM_011537118.2. [Q13114-2] DR RefSeq; XP_016877106.1; XM_017021617.1. [Q13114-1] DR RefSeq; XP_016877107.1; XM_017021618.1. [Q13114-1] DR PDB; 1FLK; X-ray; 2.80 A; A/B=341-568. DR PDB; 1FLL; X-ray; 3.50 A; A/B=341-568. DR PDB; 1KZZ; X-ray; 3.50 A; A=377-568. DR PDB; 1L0A; X-ray; 2.90 A; A=377-568. DR PDB; 1RF3; X-ray; 3.50 A; A=377-568. DR PDB; 1ZMS; X-ray; 2.80 A; A=377-568. DR PDB; 2ECY; NMR; -; A=43-101. DR PDB; 2GKW; X-ray; 2.70 A; A=377-568. DR PDB; 8T5P; X-ray; 2.50 A; A/B/C/D/E/F=377-568. DR PDBsum; 1FLK; -. DR PDBsum; 1FLL; -. DR PDBsum; 1KZZ; -. DR PDBsum; 1L0A; -. DR PDBsum; 1RF3; -. DR PDBsum; 1ZMS; -. DR PDBsum; 2ECY; -. DR PDBsum; 2GKW; -. DR PDBsum; 8T5P; -. DR AlphaFoldDB; Q13114; -. DR BMRB; Q13114; -. DR SMR; Q13114; -. DR BioGRID; 113039; 218. DR ComplexPortal; CPX-6018; STING-TRAF3-TBK1 complex. DR ComplexPortal; CPX-6037; MAVS-TRAF3 E3 ubiquitin ligase complex. DR CORUM; Q13114; -. DR DIP; DIP-6222N; -. DR IntAct; Q13114; 97. DR MINT; Q13114; -. DR STRING; 9606.ENSP00000376500; -. DR MoonDB; Q13114; Predicted. DR GlyGen; Q13114; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; Q13114; -. DR PhosphoSitePlus; Q13114; -. DR BioMuta; TRAF3; -. DR DMDM; 116242824; -. DR EPD; Q13114; -. DR jPOST; Q13114; -. DR MassIVE; Q13114; -. DR MaxQB; Q13114; -. DR PaxDb; 9606-ENSP00000454207; -. DR PeptideAtlas; Q13114; -. DR ProteomicsDB; 59165; -. [Q13114-1] DR ProteomicsDB; 59166; -. [Q13114-2] DR Pumba; Q13114; -. DR Antibodypedia; 129; 599 antibodies from 44 providers. DR CPTC; Q13114; 3 antibodies. DR DNASU; 7187; -. DR Ensembl; ENST00000392745.8; ENSP00000376500.3; ENSG00000131323.17. [Q13114-1] DR Ensembl; ENST00000539721.5; ENSP00000445998.1; ENSG00000131323.17. [Q13114-2] DR Ensembl; ENST00000560371.5; ENSP00000454207.1; ENSG00000131323.17. [Q13114-1] DR Ensembl; ENST00000699894.1; ENSP00000514678.1; ENSG00000131323.17. [Q13114-1] DR GeneID; 7187; -. DR KEGG; hsa:7187; -. DR MANE-Select; ENST00000392745.8; ENSP00000376500.3; NM_145725.3; NP_663777.1. DR UCSC; uc001ymc.3; human. [Q13114-1] DR AGR; HGNC:12033; -. DR CTD; 7187; -. DR DisGeNET; 7187; -. DR GeneCards; TRAF3; -. DR HGNC; HGNC:12033; TRAF3. DR HPA; ENSG00000131323; Low tissue specificity. DR MalaCards; TRAF3; -. DR MIM; 601896; gene. DR MIM; 614849; phenotype. DR neXtProt; NX_Q13114; -. DR OpenTargets; ENSG00000131323; -. DR Orphanet; 1930; Herpes simplex virus encephalitis. DR PharmGKB; PA36710; -. DR VEuPathDB; HostDB:ENSG00000131323; -. DR eggNOG; KOG0297; Eukaryota. DR GeneTree; ENSGT00940000160538; -. DR HOGENOM; CLU_021061_4_1_1; -. DR InParanoid; Q13114; -. DR OMA; ETVCPSF; -. DR OrthoDB; 2913784at2759; -. DR PhylomeDB; Q13114; -. DR TreeFam; TF321154; -. DR PathwayCommons; Q13114; -. DR Reactome; R-HSA-5602571; TRAF3 deficiency - HSE. DR Reactome; R-HSA-5668541; TNFR2 non-canonical NF-kB pathway. DR Reactome; R-HSA-5676594; TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway. DR Reactome; R-HSA-5689896; Ovarian tumor domain proteases. DR Reactome; R-HSA-9013973; TICAM1-dependent activation of IRF3/IRF7. DR Reactome; R-HSA-918233; TRAF3-dependent IRF activation pathway. DR Reactome; R-HSA-936440; Negative regulators of DDX58/IFIH1 signaling. DR Reactome; R-HSA-936964; Activation of IRF3, IRF7 mediated by TBK1, IKBKE. DR Reactome; R-HSA-9692916; SARS-CoV-1 activates/modulates innate immune responses. DR Reactome; R-HSA-9705671; SARS-CoV-2 activates/modulates innate and adaptive immune responses. DR SignaLink; Q13114; -. DR SIGNOR; Q13114; -. DR BioGRID-ORCS; 7187; 37 hits in 1216 CRISPR screens. DR ChiTaRS; TRAF3; human. DR EvolutionaryTrace; Q13114; -. DR GeneWiki; TRAF3; -. DR GenomeRNAi; 7187; -. DR Pharos; Q13114; Tbio. DR PRO; PR:Q13114; -. DR Proteomes; UP000005640; Chromosome 14. DR RNAct; Q13114; Protein. DR Bgee; ENSG00000131323; Expressed in cartilage tissue and 176 other cell types or tissues. DR ExpressionAtlas; Q13114; baseline and differential. DR GO; GO:0035631; C:CD40 receptor complex; ISS:BHF-UCL. DR GO; GO:0009898; C:cytoplasmic side of plasma membrane; ISS:BHF-UCL. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0005768; C:endosome; IDA:UniProt. DR GO; GO:0010008; C:endosome membrane; IDA:UniProt. DR GO; GO:0005739; C:mitochondrion; IDA:UniProt. DR GO; GO:1902554; C:serine/threonine protein kinase complex; NAS:ComplexPortal. DR GO; GO:0000151; C:ubiquitin ligase complex; NAS:ComplexPortal. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0019901; F:protein kinase binding; IEA:Ensembl. DR GO; GO:0019903; F:protein phosphatase binding; IPI:UniProtKB. DR GO; GO:0031996; F:thioesterase binding; IPI:UniProtKB. DR GO; GO:0005164; F:tumor necrosis factor receptor binding; IPI:UniProtKB. DR GO; GO:0061630; F:ubiquitin protein ligase activity; IDA:UniProt. DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:UniProtKB. DR GO; GO:0004842; F:ubiquitin-protein transferase activity; IDA:UniProt. DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro. DR GO; GO:0006915; P:apoptotic process; TAS:ProtInc. DR GO; GO:0051607; P:defense response to virus; NAS:ComplexPortal. DR GO; GO:0032088; P:negative regulation of NF-kappaB transcription factor activity; IMP:UniProtKB. DR GO; GO:0032481; P:positive regulation of type I interferon production; IDA:UniProt. DR GO; GO:0070534; P:protein K63-linked ubiquitination; IBA:GO_Central. 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:0001817; P:regulation of cytokine production; ISS:UniProtKB. DR GO; GO:0050688; P:regulation of defense response to virus; ISS:UniProtKB. DR GO; GO:0032648; P:regulation of interferon-beta production; ISS:UniProtKB. DR GO; GO:0030162; P:regulation of proteolysis; IMP:UniProtKB. DR GO; GO:0007165; P:signal transduction; TAS:ProtInc. DR GO; GO:0008063; P:Toll signaling pathway; IEA:InterPro. DR GO; GO:0034142; P:toll-like receptor 4 signaling pathway; IDA:UniProt. DR GO; GO:0002224; P:toll-like receptor signaling pathway; ISS:UniProtKB. DR GO; GO:0035666; P:TRIF-dependent toll-like receptor signaling pathway; TAS:Reactome. DR GO; GO:0033209; P:tumor necrosis factor-mediated signaling pathway; IMP:UniProtKB. DR GO; GO:0060337; P:type I interferon-mediated signaling pathway; NAS:ComplexPortal. DR CDD; cd03777; MATH_TRAF3; 1. DR CDD; cd16640; RING-HC_TRAF3; 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; IPR049440; TRAF3/5_RING. DR InterPro; IPR037304; TRAF3_MATH. DR InterPro; IPR027128; TRAF3_RING-HC. DR InterPro; IPR049342; TRAF_MEP1_MATH_dom. 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:SF76; TNF RECEPTOR-ASSOCIATED FACTOR 3; 1. DR Pfam; PF21355; TRAF-mep_MATH; 1. DR Pfam; PF21363; TRAF3_RING; 1. DR Pfam; PF02176; zf-TRAF; 1. DR PIRSF; PIRSF015614; TRAF; 1. DR SMART; SM00061; MATH; 1. DR SUPFAM; SSF57850; RING/U-box; 1. DR SUPFAM; SSF49599; TRAF domain-like; 3. DR SUPFAM; SSF57953; Trimerization domain of TRAF; 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. DR Genevisible; Q13114; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Apoptosis; Coiled coil; Cytoplasm; KW Disease variant; Endosome; Host-virus interaction; Immunity; KW Isopeptide bond; Metal-binding; Mitochondrion; Phosphoprotein; KW Reference proteome; Repeat; Thioester bond; Transferase; Ubl conjugation; KW Ubl conjugation pathway; Zinc; Zinc-finger. FT CHAIN 1..568 FT /note="TNF receptor-associated factor 3" FT /id="PRO_0000056401" FT DOMAIN 415..560 FT /note="MATH" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00129" FT ZN_FING 68..77 FT /note="RING-type" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00175" FT ZN_FING 135..190 FT /note="TRAF-type 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00207" FT ZN_FING 191..249 FT /note="TRAF-type 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00207" FT REGION 1..28 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 392..415 FT /note="(Microbial infection) Interaction with glycoprotein FT N of Andes and New York hantaviruses" FT /evidence="ECO:0000269|PubMed:24390324" FT COILED 267..338 FT /evidence="ECO:0000255" FT MOD_RES 9 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT CROSSLNK 56 FT /note="Glycyl cysteine thioester (Cys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:33608556" FT CROSSLNK 124 FT /note="Glycyl cysteine thioester (Cys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:33608556" FT CROSSLNK 168 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:27438768" FT CROSSLNK 329 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000250|UniProtKB:Q60803" FT VAR_SEQ 191..273 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_040040" FT VARIANT 118 FT /note="R -> W (in IIAE5; dbSNP:rs143813189)" FT /evidence="ECO:0000269|PubMed:20832341" FT /id="VAR_069081" FT VARIANT 129 FT /note="M -> T (in dbSNP:rs1131877)" FT /evidence="ECO:0000269|PubMed:7530216, FT ECO:0000269|PubMed:7533327" FT /id="VAR_052149" FT MUTAGEN 56 FT /note="C->A: Strong increase in both 'Lys-48' and FT 'Lys-63'-linked ubiquitination." FT /evidence="ECO:0000269|PubMed:33608556" FT MUTAGEN 68..70 FT /note="CGH->AGA: Loss of ubiquitination activity, impaired FT interaction with MAVS and IRF3. No effect on interaction FT with IKBKE, nor with DDX3X." FT /evidence="ECO:0000269|PubMed:27980081" FT MUTAGEN 68 FT /note="C->A: Loss of ubiquitination activity on ASC; when FT associated with A-70." FT /evidence="ECO:0000269|PubMed:25847972" FT MUTAGEN 70 FT /note="H->A: Loss of ubiquitination activity on ASC; when FT associated with A-68." FT /evidence="ECO:0000269|PubMed:25847972" FT MUTAGEN 124 FT /note="C->A: Strong increase in both 'Lys-48' and FT 'Lys-63'-linked ubiquitination." FT /evidence="ECO:0000269|PubMed:33608556" FT MUTAGEN 168 FT /note="K->R: Abolishes interaction with RALGDS." FT /evidence="ECO:0000269|PubMed:27438768" FT MUTAGEN 441 FT /note="Y->A: Abolishes interaction with RNF216; when FT associated with A-443." FT /evidence="ECO:0000269|PubMed:19893624" FT MUTAGEN 443 FT /note="Q->A: Abolishes interaction with RNF216; when FT associated with A-441." FT /evidence="ECO:0000269|PubMed:19893624" FT MUTAGEN 459 FT /note="Y->A: Abolishes interaction with LTBR, CD40 and FT TANK." FT /evidence="ECO:0000269|PubMed:14517219" FT MUTAGEN 462 FT /note="G->A: Confers resistance to cleavage by enterovirus FT D68 protease 2A." FT /evidence="ECO:0000269|PubMed:33148796" FT MUTAGEN 512 FT /note="F->E: Abolishes interaction with LTBR, CD40 and FT TANK." FT /evidence="ECO:0000269|PubMed:14517219" FT MUTAGEN 521 FT /note="F->A: Abolishes interaction with LTBR, CD40 and FT TANK." FT /evidence="ECO:0000269|PubMed:14517219" FT CONFLICT 134 FT /note="Missing (in Ref. 4; AAA56753)" FT /evidence="ECO:0000305" FT CONFLICT 158 FT /note="L -> F (in Ref. 6; BAH13910)" FT /evidence="ECO:0000305" FT CONFLICT 218..242 FT /note="Missing (in Ref. 3; AAA68195)" FT /evidence="ECO:0000305" FT CONFLICT 339 FT /note="P -> S (in Ref. 3; AAA68195)" FT /evidence="ECO:0000305" FT CONFLICT 405 FT /note="R -> G (in Ref. 4; AAA56753)" FT /evidence="ECO:0000305" FT TURN 54..56 FT /evidence="ECO:0007829|PDB:2ECY" FT STRAND 59..62 FT /evidence="ECO:0007829|PDB:2ECY" FT STRAND 67..69 FT /evidence="ECO:0007829|PDB:2ECY" FT HELIX 74..81 FT /evidence="ECO:0007829|PDB:2ECY" FT TURN 89..91 FT /evidence="ECO:0007829|PDB:2ECY" FT TURN 97..99 FT /evidence="ECO:0007829|PDB:2ECY" FT TURN 365..373 FT /evidence="ECO:0007829|PDB:1FLK" FT TURN 375..377 FT /evidence="ECO:0007829|PDB:1FLL" FT HELIX 378..410 FT /evidence="ECO:0007829|PDB:2GKW" FT STRAND 415..423 FT /evidence="ECO:0007829|PDB:2GKW" FT HELIX 425..433 FT /evidence="ECO:0007829|PDB:2GKW" FT STRAND 438..441 FT /evidence="ECO:0007829|PDB:1L0A" FT STRAND 445..448 FT /evidence="ECO:0007829|PDB:2GKW" FT STRAND 453..459 FT /evidence="ECO:0007829|PDB:2GKW" FT HELIX 464..466 FT /evidence="ECO:0007829|PDB:2GKW" FT TURN 467..469 FT /evidence="ECO:0007829|PDB:2GKW" FT STRAND 470..478 FT /evidence="ECO:0007829|PDB:2GKW" FT HELIX 483..485 FT /evidence="ECO:0007829|PDB:2GKW" FT STRAND 494..498 FT /evidence="ECO:0007829|PDB:2GKW" FT STRAND 502..504 FT /evidence="ECO:0007829|PDB:1FLK" FT STRAND 508..512 FT /evidence="ECO:0007829|PDB:2GKW" FT STRAND 521..523 FT /evidence="ECO:0007829|PDB:1FLK" FT STRAND 525..528 FT /evidence="ECO:0007829|PDB:2GKW" FT STRAND 532..539 FT /evidence="ECO:0007829|PDB:2GKW" FT HELIX 540..545 FT /evidence="ECO:0007829|PDB:2GKW" FT STRAND 553..560 FT /evidence="ECO:0007829|PDB:2GKW" FT STRAND 563..565 FT /evidence="ECO:0007829|PDB:1ZMS" SQ SEQUENCE 568 AA; 64490 MW; 9456E440C0A90FBF CRC64; MESSKKMDSP GALQTNPPLK LHTDRSAGTP VFVPEQGGYK EKFVKTVEDK YKCEKCHLVL CSPKQTECGH RFCESCMAAL LSSSSPKCTA CQESIVKDKV FKDNCCKREI LALQIYCRNE SRGCAEQLML GHLLVHLKND CHFEELPCVR PDCKEKVLRK DLRDHVEKAC KYREATCSHC KSQVPMIALQ KHEDTDCPCV VVSCPHKCSV QTLLRSELSA HLSECVNAPS TCSFKRYGCV FQGTNQQIKA HEASSAVQHV NLLKEWSNSL EKKVSLLQNE SVEKNKSIQS LHNQICSFEI EIERQKEMLR NNESKILHLQ RVIDSQAEKL KELDKEIRPF RQNWEEADSM KSSVESLQNR VTELESVDKS AGQVARNTGL LESQLSRHDQ MLSVHDIRLA DMDLRFQVLE TASYNGVLIW KIRDYKRRKQ EAVMGKTLSL YSQPFYTGYF GYKMCARVYL NGDGMGKGTH LSLFFVIMRG EYDALLPWPF KQKVTLMLMD QGSSRRHLGD AFKPDPNSSS FKKPTGEMNI ASGCPVFVAQ TVLENGTYIK DDTIFIKVIV DTSDLPDP //