ID TNAP3_HUMAN Reviewed; 790 AA. AC P21580; B2R767; E1P588; Q2HIX9; Q5VXQ7; Q9NSR6; DT 01-MAY-1991, integrated into UniProtKB/Swiss-Prot. DT 01-MAY-1991, sequence version 1. DT 26-JUN-2013, entry version 139. DE RecName: Full=Tumor necrosis factor alpha-induced protein 3; DE Short=TNF alpha-induced protein 3; DE EC=3.4.19.12; DE EC=6.3.2.-; DE AltName: Full=OTU domain-containing protein 7C; DE AltName: Full=Putative DNA-binding protein A20; DE AltName: Full=Zinc finger protein A20; DE Contains: DE RecName: Full=A20p50; DE Contains: DE RecName: Full=A20p37; GN Name=TNFAIP3; Synonyms=OTUD7C; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=2118515; RA Opipari A.W. Jr., Boguski M.S., Dixit V.M.; RT "The A20 cDNA induced by tumor necrosis factor alpha encodes a novel RT type of zinc finger protein."; RL J. Biol. Chem. 265:14705-14708(1990). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Trachea; 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., RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., RA 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., RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., RA Nakai K., Yada T., Nakamura Y., Ohara O., 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 [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS VAL-125; CYS-127 AND RP PRO-766. RG SeattleSNPs variation discovery resource; RL Submitted (MAR-2003) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=14574404; DOI=10.1038/nature02055; RA Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L., RA Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., RA Gilbert J.G.R., Clamp M.E., Bethel G., Milne S., Ainscough R., RA Almeida J.P., Ambrose K.D., Andrews T.D., Ashwell R.I.S., RA Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Barker D.J., RA Barlow K.F., Bates K., Beare D.M., Beasley H., Beasley O., Bird C.P., RA Blakey S.E., Bray-Allen S., Brook J., Brown A.J., Brown J.Y., RA Burford D.C., Burrill W., Burton J., Carder C., Carter N.P., RA Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V., RA Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J., RA Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., RA Ellington A.E., Evans K.A., Faulkner L., Francis M.D., Frankish A., RA Frankland J., French L., Garner P., Garnett J., Ghori M.J., RA Gilby L.M., Gillson C.J., Glithero R.J., Grafham D.V., Grant M., RA Gribble S., Griffiths C., Griffiths M.N.D., Hall R., Halls K.S., RA Hammond S., Harley J.L., Hart E.A., Heath P.D., Heathcott R., RA Holmes S.J., Howden P.J., Howe K.L., Howell G.R., Huckle E., RA Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., Joy A.A., RA Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., Langford C., RA Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., Lloyd D.M., RA Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., RA Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., RA McMurray A., Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., RA Novik K.L., Oliver K., Overton-Larty E.K., Parker A., Patel R., RA Pearce A.V., Peck A.I., Phillimore B.J.C.T., Phillips S., Plumb R.W., RA Porter K.M., Ramsey Y., Ranby S.A., Rice C.M., Ross M.T., Searle S.M., RA Sehra H.K., Sheridan E., Skuce C.D., Smith S., Smith M., Spraggon L., RA Squares S.L., Steward C.A., Sycamore N., Tamlyn-Hall G., Tester J., RA Theaker A.J., Thomas D.W., Thorpe A., Tracey A., Tromans A., Tubby B., RA Wall M., Wallis J.M., West A.P., White S.S., Whitehead S.L., RA Whittaker H., Wild A., Willey D.J., Wilmer T.E., Wood J.M., Wray P.W., RA Wyatt J.C., Young L., Younger R.M., Bentley D.R., Coulson A., RA Durbin R.M., Hubbard T., Sulston J.E., Dunham I., Rogers J., Beck S.; RT "The DNA sequence and analysis of human chromosome 6."; RL Nature 425:805-811(2003). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R., RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., RA Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. 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 RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 155-790. RC TISSUE=Testis; RX PubMed=17974005; DOI=10.1186/1471-2164-8-399; RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K., RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.; RT "The full-ORF clone resource of the German cDNA consortium."; RL BMC Genomics 8:399-399(2007). RN [8] RP FUNCTION, AND INTERACTION WITH TRAF1 AND TRAF2. RX PubMed=8692885; DOI=10.1073/pnas.93.13.6721; RA Song H.Y., Rothe M., Goeddel D.V.; RT "The tumor necrosis factor-inducible zinc finger protein A20 interacts RT with TRAF1/TRAF2 and inhibits NF-kappaB activation."; RL Proc. Natl. Acad. Sci. U.S.A. 93:6721-6725(1996). RN [9] RP FUNCTION, INTERACTION WITH YWHAZ AND YWHAH, AND MUTAGENESIS OF ARG-562 RP AND SER-565. RX PubMed=9299557; DOI=10.1006/bbrc.1997.7343; RA De Valck D., Heyninck K., Van Criekinge W., Vandenabeele P., Fiers W., RA Beyaert R.; RT "A20 inhibits NF-kappaB activation independently of binding to 14-3-3 RT proteins."; RL Biochem. Biophys. Res. Commun. 238:590-594(1997). RN [10] RP FUNCTION, AND INTERACTION WITH TRAF2. RX PubMed=9882303; RA Eliopoulos A.G., Blake S.M., Floettmann J.E., Rowe M., Young L.S.; RT "Epstein-Barr virus-encoded latent membrane protein 1 activates the RT JNK pathway through its extreme C-terminus via a mechanism involving RT TRADD and TRAF2."; RL J. Virol. 73:1023-1035(1999). RN [11] RP INTERACTION WITH TAX1BP1. RX PubMed=10435631; DOI=10.1038/sj.onc.1202787; RA de Valck D., Jin D.-Y., Heyninck K., van de Craen M., Contreras R., RA Fiers W., Jeang K.-T., Beyaert R.; RT "The zinc finger protein A20 interacts with a novel anti-apoptotic RT protein which is cleaved by specific caspases."; RL Oncogene 18:4182-4190(1999). RN [12] RP SUBCELLULAR LOCATION. RX PubMed=11463333; DOI=10.1042/0264-6021:3570617; RA Evans P.C., Taylor E.R., Coadwell J., Heyninck K., Beyaert R., RA Kilshaw P.J.; RT "Isolation and characterization of two novel A20-like proteins."; RL Biochem. J. 357:617-623(2001). RN [13] RP FUNCTION, AND MUTAGENESIS OF CYS-103. RX PubMed=14748687; DOI=10.1042/BJ20031377; RA Evans P.C., Ovaa H., Hamon M., Kilshaw P.J., Hamm S., Bauer S., RA Ploegh H.L., Smith T.S.; RT "Zinc-finger protein A20, a regulator of inflammation and cell RT survival, has de-ubiquitinating activity."; RL Biochem. J. 378:727-734(2004). RN [14] RP FUNCTION, DOMAIN OTU, DOMAIN A20-TYPE ZINC FINGER, AND MUTAGENESIS OF RP CYS-103; CYS-521; CYS-524; CYS-624 AND CYS-627. RX PubMed=15258597; DOI=10.1038/nature02794; RA Wertz I.E., O'Rourke K.M., Zhou H., Eby M., Aravind L., Seshagiri S., RA Wu P., Wiesmann C., Baker R., Boone D.L., Ma A., Koonin E.V., RA Dixit V.M.; RT "De-ubiquitination and ubiquitin ligase domains of A20 downregulate RT NF-kappaB signalling."; RL Nature 430:694-699(2004). RN [15] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026; RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., RA Mann M.; RT "Global, in vivo, and site-specific phosphorylation dynamics in RT signaling networks."; RL Cell 127:635-648(2006). RN [16] RP FUNCTION, AND INTERACTION WITH IKBKG AND TNIP1. RX PubMed=16684768; DOI=10.1074/jbc.M601502200; RA Mauro C., Pacifico F., Lavorgna A., Mellone S., Iannetti A., RA Acquaviva R., Formisano S., Vito P., Leonardi A.; RT "ABIN-1 binds to NEMO/IKKgamma and co-operates with A20 in inhibiting RT NF-kappaB."; RL J. Biol. Chem. 281:18482-18488(2006). RN [17] RP PROTEOLYTIC CLEAVAGE. RX PubMed=18223652; DOI=10.1038/ni1561; RA Coornaert B., Baens M., Heyninck K., Bekaert T., Haegman M., Staal J., RA Sun L., Chen Z.J., Marynen P., Beyaert R.; RT "T cell antigen receptor stimulation induces MALT1 paracaspase- RT mediated cleavage of the NF-kappaB inhibitor A20."; RL Nat. Immunol. 9:263-271(2008). RN [18] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [19] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=18952128; DOI=10.1016/j.bbamcr.2008.09.013; RA Li L., Soetandyo N., Wang Q., Ye Y.; RT "The zinc finger protein A20 targets TRAF2 to the lysosomes for RT degradation."; RL Biochim. Biophys. Acta 1793:346-353(2009). RN [20] RP INTERACTION WITH TAX1BP1; RNF11 AND RIPK1. RX PubMed=19131965; DOI=10.1038/emboj.2008.285; RA Shembade N., Parvatiyar K., Harhaj N.S., Harhaj E.W.; RT "The ubiquitin-editing enzyme A20 requires RNF11 to downregulate NF- RT kappaB signalling."; RL EMBO J. 28:513-522(2009). RN [21] RP FUNCTION. RX PubMed=19494296; DOI=10.4049/jimmunol.0803313; RA Duwel M., Welteke V., Oeckinghaus A., Baens M., Kloo B., Ferch U., RA Darnay B.G., Ruland J., Marynen P., Krappmann D.; RT "A20 negatively regulates T cell receptor signaling to NF-kappaB by RT cleaving Malt1 ubiquitin chains."; RL J. Immunol. 182:7718-7728(2009). RN [22] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-459, AND MASS RP SPECTROMETRY. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [23] RP PROTEOLYTIC CLEAVAGE, AND SUBCELLULAR LOCATION. RX PubMed=20804738; DOI=10.1016/j.bbrc.2010.08.091; RA Malinverni C., Unterreiner A., Staal J., Demeyer A., Galaup M., RA Luyten M., Beyaert R., Bornancin F.; RT "Cleavage by MALT1 induces cytosolic release of A20."; RL Biochem. Biophys. Res. Commun. 400:543-547(2010). RN [24] RP FUNCTION, INTERACTION WITH IKBKG, AND MUTAGENESIS OF 770-PHE-GLY-771; RP CYS-779 AND CYS-782. RX PubMed=22099304; DOI=10.1016/j.molcel.2011.09.015; RA Skaug B., Chen J., Du F., He J., Ma A., Chen Z.J.; RT "Direct, noncatalytic mechanism of IKK inhibition by A20."; RL Mol. Cell 44:559-571(2011). RN [25] RP STRUCTURE BY NMR OF 381-790. RG RIKEN structural genomics initiative (RSGI); RT "Solution structure of the A20-type zinc finger domains from human RT tumor necrosis factor, alpha-induced protein 3."; RL Submitted (OCT-2007) to the PDB data bank. RN [26] RP X-RAY CRYSTALLOGRAPHY (3.2 ANGSTROMS) OF 1-366, CATALYTIC ACTIVITY, RP FUNCTION, AND MUTAGENESIS OF ASP-70; CYS-103 AND HIS-256. RX PubMed=17961127; DOI=10.1042/BJ20071399; RA Komander D., Barford D.; RT "Structure of the A20 OTU domain and mechanistic insights into RT deubiquitination."; RL Biochem. J. 409:77-85(2008). RN [27] RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 1-370, ACTIVE SITE, CATALYTIC RP ACTIVITY, FUNCTION, AND MUTAGENESIS OF ASP-70; THR-97; ASP-100; RP CYS-103; LEU-157; TYR-159; SER-190; GLU-192; PHE-224 AND LEU-227. RX PubMed=18164316; DOI=10.1016/j.jmb.2007.11.092; RA Lin S.C., Chung J.Y., Lamothe B., Rajashankar K., Lu M., Lo Y.C., RA Lam A.Y., Darnay B.G., Wu H.; RT "Molecular basis for the unique deubiquitinating activity of the NF- RT kappaB inhibitor A20."; RL J. Mol. Biol. 376:526-540(2008). RN [28] RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 592-635 IN COMPLEX WITH RP UBIQUITIN, X-RAY CRYSTALLOGRAPHY (3.4 ANGSTROMS) OF 592-635 IN COMPLEX RP WITH UBIQUITIN AND UBE2D1, AND MUTAGENESIS OF TYR-614; PHE-615 AND RP LEU-626. RX PubMed=21095585; DOI=10.1016/j.molcel.2010.10.009; RA Bosanac I., Wertz I.E., Pan B., Yu C., Kusam S., Lam C., Phu L., RA Phung Q., Maurer B., Arnott D., Kirkpatrick D.S., Dixit V.M., RA Hymowitz S.G.; RT "Ubiquitin binding to A20 ZnF4 is required for modulation of NF-kappaB RT signaling."; RL Mol. Cell 40:548-557(2010). CC -!- FUNCTION: Ubiquitin-editing enzyme that contains both ubiquitin CC ligase and deubiquitinase activities. Involved in immune and CC inflammatory responses signaled by cytokines, such as TNF-alpha CC and IL-1 beta, or pathogens via Toll-like receptors (TLRs) through CC terminating NF-kappa-B activity. Essential component of a CC ubiquitin-editing protein complex, comprising also RNF11, ITCH and CC TAX1BP1, that ensures the transient nature of inflammatory CC signaling pathways. In cooperation with TAX1BP1 promotes CC disassembly of E2-E3 ubiquitin protein ligase complexes in IL-1R CC and TNFR-1 pathways; affected are at least E3 ligases TRAF6, TRAF2 CC and BIRC2, and E2 ubiquitin-conjugating enzymes UBE2N and UBE2D3. CC In cooperation with TAX1BP1 promotes ubiquitination of UBE2N and CC proteasomal degradation of UBE2N and UBE2D3. Upon TNF stimulation, CC deubiquitinates 'Lys-63'-polyubiquitin chains on RIPK1 and CC catalyzes the formation of 'Lys-48'-polyubiquitin chains. This CC leads to RIPK1 proteasomal degradation and consequently CC termination of the TNF- or LPS-mediated activation of NF-kappa-B. CC Deubiquinates TRAF6 probably acting on 'Lys-63'-linked CC polyubiquitin. Upon T-cell receptor (TCR)-mediated T-cell CC activation, deubiquitinates 'Lys-63'-polyubiquitin chains on MALT1 CC thereby mediating disassociation of the CBM (CARD11:BCL10:MALT1) CC and IKK complexes and preventing sustained IKK activation. CC Deubiquinates NEMO/IKBKG; the function is facilitated by TNIP1 and CC leads to inhibition of NF-kappa-B activation. Upon stimulation by CC bacterial peptidoglycans, probably deubiquitinates RIPK2. Can also CC inhibit I-kappa-B-kinase (IKK) through a non-catalytic mechanism CC which involves polyubiquitin; polyubiquitin promotes association CC with IKBKG and prevents IKK MAP3K7-mediated phosphorylation. CC Targets TRAF2 for lysosomal degradation. In vitro able to CC deubiquitinate both 'Lys-48'- and 'Lys-63' polyubiquitin chains. CC Inhibitor of programmed cell death. Has a role in the function of CC the lymphoid system. CC -!- CATALYTIC ACTIVITY: Thiol-dependent hydrolysis of ester, CC thioester, amide, peptide and isopeptide bonds formed by the C- CC terminal Gly of ubiquitin (a 76-residue protein attached to CC proteins as an intracellular targeting signal). CC -!- SUBUNIT: Homodimer. Interacts with TNIP1, TAX1BP1 and TRAF2. CC Interacts with RNF11, ITCH and TAX1BP1 only after TNF stimulation; CC these interaction are transient and they are lost after 1 hour of CC stimulation with TNF (By similarity). Interacts with YWHAZ and CC YWHAH. Interacts with IKBKG; the interaction is induced by TNF CC stimulation and by polyubiquitin. Interacts with RIPK1. Interacts CC with UBE2N; the interaction requires TAX1BP1. Interacts with CC TRAF6; the interaction is inhibited by HTLV-1 protein Tax. CC -!- INTERACTION: CC Q9Y6K9:IKBKG; NbExp=2; IntAct=EBI-527670, EBI-81279; CC P68510:Ywhah (xeno); NbExp=3; IntAct=EBI-527670, EBI-444641; CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Lysosome. CC -!- SUBCELLULAR LOCATION: A20p50: Cytoplasm. CC -!- INDUCTION: By TNF. CC -!- DOMAIN: The A20-type zinc fingers mediate the ubiquitin ligase CC activity. The A20-type zinc finger 4 selectively recognizes 'Lys- CC 63'-linked polyubiquitin. The A20-type zinc finger 4-7 are CC sufficient to bind polyubiquitin. CC -!- DOMAIN: The OTU domain mediates the deubiquitinase activity. CC -!- PTM: Proteolytically cleaved by MALT1 upon TCR stimulation; CC disrupts NF-kappa-B inhibitory function and results in increased CC IL-2 production. It is proposed that only a fraction of TNFAIP3 CC colocalized with TCR and CBM complex is cleaved, leaving the main CC TNFAIP3 pool intact. CC -!- SIMILARITY: Belongs to the peptidase C64 family. CC -!- SIMILARITY: Contains 7 A20-type zinc fingers. CC -!- SIMILARITY: Contains 1 OTU domain. CC -!- WEB RESOURCE: Name=SeattleSNPs; CC URL="http://pga.gs.washington.edu/data/tnfaip3/"; CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology CC and Haematology; CC URL="http://atlasgeneticsoncology.org/Genes/TNFAIP3ID42600ch6q23.html"; 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; M59465; AAA51550.1; -; mRNA. DR EMBL; AK312862; BAG35714.1; -; mRNA. DR EMBL; AY248754; AAO61093.1; -; Genomic_DNA. DR EMBL; AL357060; CAH72937.1; -; Genomic_DNA. DR EMBL; CH471051; EAW47925.1; -; Genomic_DNA. DR EMBL; CH471051; EAW47926.1; -; Genomic_DNA. DR EMBL; BC113871; AAI13872.1; -; mRNA. DR EMBL; BC114480; AAI14481.1; -; mRNA. DR EMBL; AL157444; CAB75664.1; -; mRNA. DR IPI; IPI00009448; -. DR PIR; A35797; A35797. DR RefSeq; NP_001257436.1; NM_001270507.1. DR RefSeq; NP_001257437.1; NM_001270508.1. DR RefSeq; NP_006281.1; NM_006290.3. DR UniGene; Hs.211600; -. DR PDB; 2EQE; NMR; -; A=597-631. DR PDB; 2EQF; NMR; -; A=758-790. DR PDB; 2EQG; NMR; -; A=381-416. DR PDB; 2VFJ; X-ray; 3.20 A; A/B/C/D=1-366. DR PDB; 3DKB; X-ray; 2.50 A; A/B/C/D/E/F=1-370. DR PDB; 3OJ3; X-ray; 2.50 A; I/J/K/L/M/N/O/P=592-635. DR PDB; 3OJ4; X-ray; 3.40 A; C/F=592-635. DR PDB; 3VUW; X-ray; 1.95 A; E/F/G=757-789. DR PDB; 3VUX; X-ray; 1.70 A; E/F/G=757-790. DR PDB; 3VUY; X-ray; 1.98 A; D/E/F=757-790. DR PDB; 3ZJD; X-ray; 1.87 A; A/B=1-366. DR PDB; 3ZJE; X-ray; 1.84 A; A/B=1-366. DR PDB; 3ZJF; X-ray; 2.20 A; A/B=1-366. DR PDB; 3ZJG; X-ray; 1.92 A; A/B=1-366. DR PDBsum; 2EQE; -. DR PDBsum; 2EQF; -. DR PDBsum; 2EQG; -. DR PDBsum; 2VFJ; -. DR PDBsum; 3DKB; -. DR PDBsum; 3OJ3; -. DR PDBsum; 3OJ4; -. DR PDBsum; 3VUW; -. DR PDBsum; 3VUX; -. DR PDBsum; 3VUY; -. DR PDBsum; 3ZJD; -. DR PDBsum; 3ZJE; -. DR PDBsum; 3ZJF; -. DR PDBsum; 3ZJG; -. DR ProteinModelPortal; P21580; -. DR DIP; DIP-33804N; -. DR IntAct; P21580; 13. DR MINT; MINT-97330; -. DR STRING; 9606.ENSP00000237289; -. DR MEROPS; C64.003; -. DR PhosphoSite; P21580; -. DR DMDM; 112894; -. DR PaxDb; P21580; -. DR PRIDE; P21580; -. DR Ensembl; ENST00000237289; ENSP00000237289; ENSG00000118503. DR GeneID; 7128; -. DR KEGG; hsa:7128; -. DR UCSC; uc003qhr.3; human. DR CTD; 7128; -. DR GeneCards; GC06P138188; -. DR HGNC; HGNC:11896; TNFAIP3. DR HPA; HPA002116; -. DR MIM; 191163; gene. DR neXtProt; NX_P21580; -. DR PharmGKB; PA36593; -. DR eggNOG; NOG248343; -. DR HOGENOM; HOG000133004; -. DR HOVERGEN; HBG059260; -. DR InParanoid; P21580; -. DR KO; K11859; -. DR OMA; CETPNCP; -. DR OrthoDB; EOG4XD3QK; -. DR Pathway_Interaction_DB; nfkappabcanonicalpathway; Canonical NF-kappaB pathway. DR Pathway_Interaction_DB; tnfpathway; TNF receptor signaling pathway. DR Reactome; REACT_6900; Immune System. DR SignaLink; P21580; -. DR ChiTaRS; TNFAIP3; human. DR EvolutionaryTrace; P21580; -. DR GenomeRNAi; 7128; -. DR NextBio; 27895; -. DR ArrayExpress; P21580; -. DR Bgee; P21580; -. DR CleanEx; HS_TNFAIP3; -. DR Genevestigator; P21580; -. DR GermOnline; ENSG00000118503; Homo sapiens. DR GO; GO:0005813; C:centrosome; IDA:HPA. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0005764; C:lysosome; IEA:UniProtKB-SubCell. DR GO; GO:0005634; C:nucleus; IDA:HGNC. DR GO; GO:0043027; F:cysteine-type endopeptidase inhibitor activity involved in apoptotic process; NAS:BHF-UCL. DR GO; GO:0003677; F:DNA binding; IEA:UniProtKB-KW. DR GO; GO:0043621; F:protein self-association; IDA:BHF-UCL. DR GO; GO:0004221; F:ubiquitin thiolesterase activity; IMP:UniProtKB. DR GO; GO:0004842; F:ubiquitin-protein ligase activity; IDA:UniProtKB. DR GO; GO:0004843; F:ubiquitin-specific protease activity; IDA:UniProtKB. DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro. DR GO; GO:0001922; P:B-1 B cell homeostasis; ISS:BHF-UCL. DR GO; GO:0070301; P:cellular response to hydrogen peroxide; ISS:UniProtKB. DR GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW. DR GO; GO:0045087; P:innate immune response; TAS:Reactome. DR GO; GO:0050869; P:negative regulation of B cell activation; ISS:BHF-UCL. DR GO; GO:0045779; P:negative regulation of bone resorption; NAS:BHF-UCL. DR GO; GO:2000349; P:negative regulation of CD40 signaling pathway; IMP:BHF-UCL. DR GO; GO:0002677; P:negative regulation of chronic inflammatory response; IEA:Compara. DR GO; GO:0045736; P:negative regulation of cyclin-dependent protein serine/threonine kinase activity; IEA:Compara. DR GO; GO:2000352; P:negative regulation of endothelial cell apoptotic process; IDA:BHF-UCL. DR GO; GO:0043124; P:negative regulation of I-kappaB kinase/NF-kappaB cascade; IDA:UniProtKB. DR GO; GO:0050728; P:negative regulation of inflammatory response; ISS:BHF-UCL. DR GO; GO:0045824; P:negative regulation of innate immune response; ISS:UniProtKB. DR GO; GO:0032691; P:negative regulation of interleukin-1 beta production; IEA:Compara. DR GO; GO:0032703; P:negative regulation of interleukin-2 production; IMP:BHF-UCL. DR GO; GO:0032715; P:negative regulation of interleukin-6 production; ISS:BHF-UCL. DR GO; GO:0032088; P:negative regulation of NF-kappaB transcription factor activity; IDA:BHF-UCL. DR GO; GO:0070429; P:negative regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway; IEA:Compara. DR GO; GO:0070433; P:negative regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway; IEA:Compara. DR GO; GO:0090291; P:negative regulation of osteoclast proliferation; NAS:BHF-UCL. DR GO; GO:0031397; P:negative regulation of protein ubiquitination; IDA:BHF-UCL. DR GO; GO:0048662; P:negative regulation of smooth muscle cell proliferation; IDA:BHF-UCL. DR GO; GO:0034136; P:negative regulation of toll-like receptor 2 signaling pathway; NAS:BHF-UCL. DR GO; GO:0034140; P:negative regulation of toll-like receptor 3 signaling pathway; IDA:BHF-UCL. DR GO; GO:0034148; P:negative regulation of toll-like receptor 5 signaling pathway; IEA:Compara. DR GO; GO:0032720; P:negative regulation of tumor necrosis factor production; ISS:BHF-UCL. DR GO; GO:0032480; P:negative regulation of type I interferon production; TAS:Reactome. DR GO; GO:0070423; P:nucleotide-binding oligomerization domain containing signaling pathway; TAS:Reactome. DR GO; GO:2000347; P:positive regulation of hepatocyte proliferation; IEA:Compara. DR GO; GO:0045732; P:positive regulation of protein catabolic process; IDA:BHF-UCL. DR GO; GO:0070936; P:protein K48-linked ubiquitination; IDA:UniProtKB. DR GO; GO:0070536; P:protein K63-linked deubiquitination; IDA:UniProtKB. DR GO; GO:0051259; P:protein oligomerization; NAS:BHF-UCL. DR GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW. DR GO; GO:0050691; P:regulation of defense response to virus by host; NAS:BHF-UCL. DR GO; GO:0002634; P:regulation of germinal center formation; ISS:BHF-UCL. DR GO; GO:0061043; P:regulation of vascular wound healing; NAS:BHF-UCL. DR GO; GO:0032495; P:response to muramyl dipeptide; IEA:Compara. DR GO; GO:0072573; P:tolerance induction to lipopolysaccharide; IMP:BHF-UCL. DR InterPro; IPR003323; OTU. DR InterPro; IPR002653; Znf_A20. DR Pfam; PF02338; OTU; 1. DR Pfam; PF01754; zf-A20; 6. DR SMART; SM00259; ZnF_A20; 7. DR PROSITE; PS50802; OTU; 1. DR PROSITE; PS51036; ZF_A20; 7. PE 1: Evidence at protein level; KW 3D-structure; Apoptosis; Complete proteome; Cytoplasm; DNA-binding; KW Hydrolase; Inflammatory response; Ligase; Lysosome; Metal-binding; KW Multifunctional enzyme; Nucleus; Phosphoprotein; Polymorphism; KW Protease; Reference proteome; Repeat; Thiol protease; KW Ubl conjugation pathway; Zinc; Zinc-finger. FT CHAIN 1 790 Tumor necrosis factor alpha-induced FT protein 3. FT /FTId=PRO_0000188791. FT CHAIN 1 439 A20p50. FT /FTId=PRO_0000418127. FT CHAIN 440 790 A20p37. FT /FTId=PRO_0000418128. FT DOMAIN 92 263 OTU. FT REPEAT 286 317 1. FT REPEAT 324 356 2. FT ZN_FING 381 416 A20-type 1. FT ZN_FING 472 507 A20-type 2. FT ZN_FING 515 548 A20-type 3. FT ZN_FING 601 636 A20-type 4. FT ZN_FING 651 686 A20-type 5. FT ZN_FING 710 745 A20-type 6. FT ZN_FING 756 790 A20-type 7. FT REGION 58 300 TRAF-binding. FT REGION 157 159 Interaction with ubiquitin (Probable). FT REGION 190 192 Interaction with ubiquitin (Probable). FT REGION 224 227 Interaction with ubiquitin (Probable). FT REGION 286 356 2 X approximate repeats. FT REGION 369 775 Interaction with TNIP1 (By similarity). FT REGION 386 453 Interaction with RIPK1. FT REGION 605 655 Required for proteosomal degradation of FT UBE2N and UBE2D3, TRAF6 deubiquitination, FT and TAX1BP1 interaction with UBE2N (By FT similarity). FT REGION 606 790 Sufficient for inhibitory activity of FT TNF-induced NF-kappa-B activity (By FT similarity). FT REGION 697 790 Required for lysosomal localization and FT for TRAF2 lysosomal degradation. FT ACT_SITE 103 103 Nucleophile. FT ACT_SITE 256 256 Proton acceptor (Probable). FT SITE 439 440 Cleavage; by MALT1. FT MOD_RES 459 459 Phosphoserine. FT VARIANT 125 125 A -> V (in dbSNP:rs5029941). FT /FTId=VAR_020447. FT VARIANT 127 127 F -> C (in dbSNP:rs2230926). FT /FTId=VAR_022143. FT VARIANT 766 766 A -> P (in dbSNP:rs5029957). FT /FTId=VAR_029319. FT MUTAGEN 70 70 D->A: Minor effect on 'Lys-48' FT deubiquitinase activity. Strongly reduced FT 'Lys-63' deubiquitinase activity. FT MUTAGEN 97 97 T->A: Minor effect on 'Lys-48' FT deubiquitinase activity. FT MUTAGEN 100 100 D->A: Strongly reduced deubiquitinase FT activity. FT MUTAGEN 103 103 C->A: Loss of deubiquitinase activity. FT MUTAGEN 103 103 C->S: Loss of 'Lys-63' deubiquitinating FT activity. Down-regulation of TNF-induced FT NF-kappa-B activity less effective. FT MUTAGEN 157 157 L->A: Strongly reduced 'Lys-48' FT deubiquitinase activity. FT MUTAGEN 159 159 Y->A: Strongly reduced 'Lys-48' FT deubiquitinase activity. FT MUTAGEN 190 190 S->A: Strongly reduced 'Lys-48' FT deubiquitinase activity. FT MUTAGEN 192 192 E->A: Strongly reduced 'Lys-48' FT deubiquitinase activity. FT MUTAGEN 224 224 F->A: Strongly reduced 'Lys-48' FT deubiquitinase activity. FT MUTAGEN 227 227 L->A: Strongly reduced 'Lys-48' FT deubiquitinase activity. FT MUTAGEN 256 256 H->A: Loss of deubiquitinase activity. FT MUTAGEN 521 521 C->A: No effect on ubiquitin ligase FT activity; when associated with A-524. FT MUTAGEN 524 524 C->A: No effect on ubiquitin ligase FT activity; when associated with A-521. FT MUTAGEN 562 562 R->A: Abolishes interactionj with YWHAZ FT AND YWHAH; no effect on inhibitory FT activity of TNF-induced NF-kappa-B FT activation. FT MUTAGEN 565 565 S->A: Abolishes interactionj with YWHAZ FT AND YWHAH; no effect on inhibitory FT activity of TNF-induced NF-kappa-B FT activation. FT MUTAGEN 614 614 Y->A: Impairs ubiquitination activity. FT Loss of down-regulation of NF-kappa-B FT activity; when associated with A-615 or FT R-626. FT MUTAGEN 615 615 F->A: Impairs ubiquitination activity. FT Loss of down-regulation of NF-kappa-B FT activity; when associated with A-614. FT MUTAGEN 624 624 C->A: Marked attenuation of ubiquitin FT ligase activity and inhibition of RIPK1 FT degradation; when associated with A-627. FT MUTAGEN 626 626 L->R: Impairs ubiquitination activity. FT Loss of down-regulation of NF-kappa-B FT activity; when associated with A-614. FT MUTAGEN 627 627 C->A: Marked attenuation of ubiquitin FT ligase activity and inhibition of RIPK1 FT degradation; when associated with A-624. FT MUTAGEN 770 771 FG->AA: Impairs polyubiquitin binding, FT abolishes inhibition of IKK activation. FT MUTAGEN 779 779 C->A: Impairs polyubiquitin binding, FT abolishes inhibition of IKK activation; FT when associated with A-782. FT MUTAGEN 782 782 C->A: Impairs polyubiquitin binding, FT abolishes inhibition of IKK activation; FT when associated with A-779. FT HELIX 10 13 FT HELIX 15 27 FT STRAND 33 35 FT STRAND 39 42 FT HELIX 43 45 FT HELIX 58 68 FT HELIX 71 79 FT STRAND 82 84 FT STRAND 87 89 FT STRAND 92 95 FT HELIX 103 113 FT HELIX 121 132 FT HELIX 136 147 FT HELIX 164 174 FT STRAND 176 178 FT STRAND 181 185 FT HELIX 193 203 FT STRAND 207 211 FT STRAND 231 233 FT HELIX 240 242 FT STRAND 248 253 FT STRAND 256 263 FT STRAND 265 268 FT STRAND 272 279 FT STRAND 282 285 FT HELIX 293 297 FT HELIX 299 306 FT STRAND 309 315 FT STRAND 317 329 FT HELIX 337 339 FT HELIX 341 354 FT HELIX 359 361 FT STRAND 384 386 FT TURN 398 402 FT HELIX 405 412 FT STRAND 604 606 FT STRAND 613 615 FT HELIX 618 620 FT HELIX 625 634 FT HELIX 773 775 FT HELIX 780 788 SQ SEQUENCE 790 AA; 89614 MW; 320AEA97F58D4491 CRC64; MAEQVLPQAL YLSNMRKAVK IRERTPEDIF KPTNGIIHHF KTMHRYTLEM FRTCQFCPQF REIIHKALID RNIQATLESQ KKLNWCREVR KLVALKTNGD GNCLMHATSQ YMWGVQDTDL VLRKALFSTL KETDTRNFKF RWQLESLKSQ EFVETGLCYD TRNWNDEWDN LIKMASTDTP MARSGLQYNS LEEIHIFVLC NILRRPIIVI SDKMLRSLES GSNFAPLKVG GIYLPLHWPA QECYRYPIVL GYDSHHFVPL VTLKDSGPEI RAVPLVNRDR GRFEDLKVHF LTDPENEMKE KLLKEYLMVI EIPVQGWDHG TTHLINAAKL DEANLPKEIN LVDDYFELVQ HEYKKWQENS EQGRREGHAQ NPMEPSVPQL SLMDVKCETP NCPFFMSVNT QPLCHECSER RQKNQNKLPK LNSKPGPEGL PGMALGASRG EAYEPLAWNP EESTGGPHSA PPTAPSPFLF SETTAMKCRS PGCPFTLNVQ HNGFCERCHN ARQLHASHAP DHTRHLDPGK CQACLQDVTR TFNGICSTCF KRTTAEASSS LSTSLPPSCH QRSKSDPSRL VRSPSPHSCH RAGNDAPAGC LSQAARTPGD RTGTSKCRKA GCVYFGTPEN KGFCTLCFIE YRENKHFAAA SGKVSPTASR FQNTIPCLGR ECGTLGSTMF EGYCQKCFIE AQNQRFHEAK RTEEQLRSSQ RRDVPRTTQS TSRPKCARAS CKNILACRSE ELCMECQHPN QRMGPGAHRG EPAPEDPPKQ RCRAPACDHF GNAKCNGYCN ECFQFKQMYG //