TNAP3_HUMAN
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 03-AUG-2022, entry version 217.
DE RecName: Full=Tumor necrosis factor alpha-induced protein 3;
DE Short=TNF alpha-induced protein 3;
DE EC=2.3.2.-;
DE EC=3.4.19.12 {ECO:0000269|PubMed:14748687, ECO:0000269|PubMed:17961127, ECO:0000269|PubMed:18164316, ECO:0000269|PubMed:23827681, ECO:0000269|PubMed:27732584};
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; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=2118515; DOI=10.1016/s0021-9258(18)77165-2;
RA Opipari A.W. Jr., Boguski M.S., Dixit V.M.;
RT "The A20 cDNA induced by tumor necrosis factor alpha encodes a novel type
RT 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., 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 [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., Gilbert J.G.R.,
RA Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D.,
RA Andrews T.D., Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H.,
RA Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J.,
RA Brown J.Y., 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., Ellington A.E.,
RA Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J.,
RA French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J.,
RA Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C.,
RA Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A.,
RA Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R.,
RA Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M.,
RA Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K.,
RA Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R.,
RA Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M.,
RA Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A.,
RA Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L.,
RA Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I.,
RA Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y.,
RA Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E.,
RA Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A.,
RA Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W.,
RA Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M.,
RA West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J.,
RA Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M.,
RA Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I.,
RA 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., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., 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 project:
RT 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., Heubner D.,
RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A.,
RA 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 with
RT 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 AND
RP 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; DOI=10.1128/jvi.73.2.1023-1035.1999;
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 JNK
RT pathway through its extreme C-terminus via a mechanism involving TRADD and
RT 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 protein
RT 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, MUTAGENESIS OF CYS-103, AND CATALYTIC ACTIVITY.
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 survival,
RT 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., Dixit V.M.;
RT "De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-
RT 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., Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in signaling
RT 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., Acquaviva R.,
RA Formisano S., Vito P., Leonardi A.;
RT "ABIN-1 binds to NEMO/IKKgamma and co-operates with A20 in inhibiting NF-
RT 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-mediated
RT 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-kappaB
RT 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 IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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., Luyten M.,
RA 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 ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR
RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E.,
RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-terminal
RT acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [26]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=23827681; DOI=10.1016/j.cell.2013.05.046;
RA Mevissen T.E., Hospenthal M.K., Geurink P.P., Elliott P.R., Akutsu M.,
RA Arnaudo N., Ekkebus R., Kulathu Y., Wauer T., El Oualid F., Freund S.M.,
RA Ovaa H., Komander D.;
RT "OTU deubiquitinases reveal mechanisms of linkage specificity and enable
RT ubiquitin chain restriction analysis.";
RL Cell 154:169-184(2013).
RN [27]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-645, AND IDENTIFICATION BY
RP MASS 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 [28]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-575, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [29]
RP INVOLVEMENT IN AISBL.
RX PubMed=26642243; DOI=10.1038/ng.3459;
RA Zhou Q., Wang H., Schwartz D.M., Stoffels M., Park Y.H., Zhang Y., Yang D.,
RA Demirkaya E., Takeuchi M., Tsai W.L., Lyons J.J., Yu X., Ouyang C.,
RA Chen C., Chin D.T., Zaal K., Chandrasekharappa S.C., P Hanson E., Yu Z.,
RA Mullikin J.C., Hasni S.A., Wertz I.E., Ombrello A.K., Stone D.L.,
RA Hoffmann P., Jones A., Barham B.K., Leavis H.L., van Royen-Kerkof A.,
RA Sibley C., Batu E.D., Guel A., Siegel R.M., Boehm M., Milner J.D., Ozen S.,
RA Gadina M., Chae J., Laxer R.M., Kastner D.L., Aksentijevich I.;
RT "Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency
RT cause an early-onset autoinflammatory disease.";
RL Nat. Genet. 48:67-73(2016).
RN [30]
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 tumor
RT necrosis factor, alpha-induced protein 3.";
RL Submitted (OCT-2007) to the PDB data bank.
RN [31]
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 [32]
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; CYS-103;
RP 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., Lam A.Y.,
RA Darnay B.G., Wu H.;
RT "Molecular basis for the unique deubiquitinating activity of the NF-kappaB
RT inhibitor A20.";
RL J. Mol. Biol. 376:526-540(2008).
RN [33]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 592-635 IN COMPLEX WITH UBIQUITIN,
RP X-RAY CRYSTALLOGRAPHY (3.4 ANGSTROMS) OF 592-635 IN COMPLEX WITH UBIQUITIN
RP AND UBE2D1, AND MUTAGENESIS OF TYR-614; PHE-615 AND 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., Phung Q.,
RA Maurer B., Arnott D., Kirkpatrick D.S., Dixit V.M., 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).
RN [34] {ECO:0007744|PDB:5LRX}
RP X-RAY CRYSTALLOGRAPHY (2.85 ANGSTROMS) OF 1-366, CATALYTIC ACTIVITY, AND
RP MUTAGENESIS OF HIS-106 AND HIS-256.
RX PubMed=27732584; DOI=10.1038/nature19836;
RA Mevissen T.E., Kulathu Y., Mulder M.P., Geurink P.P., Maslen S.L.,
RA Gersch M., Elliott P.R., Burke J.E., van Tol B.D., Akutsu M., El Oualid F.,
RA Kawasaki M., Freund S.M., Ovaa H., Komander D.;
RT "Molecular basis of Lys11-polyubiquitin specificity in the deubiquitinase
RT Cezanne.";
RL Nature 538:402-405(2016).
RN [35]
RP VARIANT AISBL TYR-243, AND CHARACTERIZATION OF VARIANT AISBL TYR-243.
RX PubMed=27175295; DOI=10.1136/rmdopen-2015-000223;
RA Shigemura T., Kaneko N., Kobayashi N., Kobayashi K., Takeuchi Y.,
RA Nakano N., Masumoto J., Agematsu K.;
RT "Novel heterozygous C243Y A20/TNFAIP3 gene mutation is responsible for
RT chronic inflammation in autosomal-dominant Behcet's disease.";
RL RMD Open 2:E000223-E000223(2016).
CC -!- FUNCTION: Ubiquitin-editing enzyme that contains both ubiquitin ligase
CC and deubiquitinase activities. Involved in immune and inflammatory
CC responses signaled by cytokines, such as TNF-alpha and IL-1 beta, or
CC pathogens via Toll-like receptors (TLRs) through terminating NF-kappa-B
CC activity. Essential component of a ubiquitin-editing protein complex,
CC comprising also RNF11, ITCH and TAX1BP1, that ensures the transient
CC nature of inflammatory signaling pathways. In cooperation with TAX1BP1
CC promotes disassembly of E2-E3 ubiquitin protein ligase complexes in IL-
CC 1R and TNFR-1 pathways; affected are at least E3 ligases TRAF6, TRAF2
CC and BIRC2, and E2 ubiquitin-conjugating enzymes UBE2N and UBE2D3. In
CC 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 catalyzes
CC the formation of 'Lys-48'-polyubiquitin chains. This leads to RIPK1
CC proteasomal degradation and consequently termination of the TNF- or
CC LPS-mediated activation of NF-kappa-B. Deubiquitinates TRAF6 probably
CC acting on 'Lys-63'-linked polyubiquitin. Upon T-cell receptor (TCR)-
CC mediated T-cell activation, deubiquitinates 'Lys-63'-polyubiquitin
CC chains on MALT1 thereby mediating disassociation of the CBM
CC (CARD11:BCL10:MALT1) and IKK complexes and preventing sustained IKK
CC activation. Deubiquitinates NEMO/IKBKG; the function is facilitated by
CC TNIP1 and leads to inhibition of NF-kappa-B activation. Upon
CC stimulation by bacterial peptidoglycans, probably deubiquitinates
CC RIPK2. Can also inhibit I-kappa-B-kinase (IKK) through a non-catalytic
CC mechanism which involves polyubiquitin; polyubiquitin promotes
CC association with IKBKG and prevents IKK MAP3K7-mediated
CC phosphorylation. Targets TRAF2 for lysosomal degradation. In vitro able
CC to deubiquitinate 'Lys-11'-, 'Lys-48'- and 'Lys-63' polyubiquitin
CC chains. Inhibitor of programmed cell death. Has a role in the function
CC of the lymphoid system. Required for LPS-induced production of pro-
CC inflammatory cytokines and IFN beta in LPS-tolerized macrophages.
CC {ECO:0000269|PubMed:14748687, ECO:0000269|PubMed:15258597,
CC ECO:0000269|PubMed:16684768, ECO:0000269|PubMed:17961127,
CC ECO:0000269|PubMed:18164316, ECO:0000269|PubMed:18952128,
CC ECO:0000269|PubMed:19494296, ECO:0000269|PubMed:22099304,
CC ECO:0000269|PubMed:23827681, ECO:0000269|PubMed:8692885,
CC ECO:0000269|PubMed:9299557, ECO:0000269|PubMed:9882303}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Thiol-dependent hydrolysis of ester, thioester, amide, peptide
CC and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76-
CC residue protein attached to proteins as an intracellular targeting
CC signal).; EC=3.4.19.12; Evidence={ECO:0000269|PubMed:14748687,
CC ECO:0000269|PubMed:17961127, ECO:0000269|PubMed:18164316,
CC ECO:0000269|PubMed:23827681, ECO:0000269|PubMed:27732584};
CC -!- SUBUNIT: Homodimer. Interacts with TNIP1, TAX1BP1 and TRAF2. Interacts
CC with RNF11, ITCH and TAX1BP1 only after TNF stimulation; these
CC interaction are transient and they are lost after 1 hour of stimulation
CC with TNF (By similarity). Interacts with YWHAZ and YWHAH. Interacts
CC with IKBKG; the interaction is induced by TNF stimulation and by
CC polyubiquitin. Interacts with RIPK1. Interacts with UBE2N; the
CC interaction requires TAX1BP1. Interacts with TRAF6; the interaction is
CC inhibited by HTLV-1 protein Tax. {ECO:0000250,
CC ECO:0000269|PubMed:10435631, ECO:0000269|PubMed:16684768,
CC ECO:0000269|PubMed:19131965, ECO:0000269|PubMed:21095585,
CC ECO:0000269|PubMed:22099304, ECO:0000269|PubMed:8692885,
CC ECO:0000269|PubMed:9299557, ECO:0000269|PubMed:9882303}.
CC -!- INTERACTION:
CC P21580; Q96B67: ARRDC3; NbExp=6; IntAct=EBI-527670, EBI-2875665;
CC P21580; Q14790: CASP8; NbExp=3; IntAct=EBI-527670, EBI-78060;
CC P21580; O95995: GAS8; NbExp=3; IntAct=EBI-527670, EBI-1052570;
CC P21580; Q9Y6K9: IKBKG; NbExp=5; IntAct=EBI-527670, EBI-81279;
CC P21580; Q8TBB1: LNX1; NbExp=3; IntAct=EBI-527670, EBI-739832;
CC P21580; Q4G0R1: PIBF1; NbExp=3; IntAct=EBI-527670, EBI-14066006;
CC P21580; P54725: RAD23A; NbExp=3; IntAct=EBI-527670, EBI-746453;
CC P21580; Q9Y3C5: RNF11; NbExp=2; IntAct=EBI-527670, EBI-396669;
CC P21580; Q9NWF9: RNF216; NbExp=3; IntAct=EBI-527670, EBI-723313;
CC P21580; Q86VP1: TAX1BP1; NbExp=5; IntAct=EBI-527670, EBI-529518;
CC P21580; P21580: TNFAIP3; NbExp=8; IntAct=EBI-527670, EBI-527670;
CC P21580; Q15025: TNIP1; NbExp=11; IntAct=EBI-527670, EBI-357849;
CC P21580; Q8NFZ5: TNIP2; NbExp=4; IntAct=EBI-527670, EBI-359372;
CC P21580; Q96KP6: TNIP3; NbExp=3; IntAct=EBI-527670, EBI-2509913;
CC P21580; Q12933: TRAF2; NbExp=10; IntAct=EBI-527670, EBI-355744;
CC P21580; P36406: TRIM23; NbExp=6; IntAct=EBI-527670, EBI-740098;
CC P21580; 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-63'-
CC linked polyubiquitin. The A20-type zinc finger 4-7 are sufficient to
CC bind polyubiquitin. {ECO:0000269|PubMed:15258597}.
CC -!- DOMAIN: The OTU domain mediates the deubiquitinase activity.
CC {ECO:0000269|PubMed:15258597}.
CC -!- PTM: Proteolytically cleaved by MALT1 upon TCR stimulation; disrupts
CC NF-kappa-B inhibitory function and results in increased IL-2
CC production. It is proposed that only a fraction of TNFAIP3 colocalized
CC with TCR and CBM complex is cleaved, leaving the main TNFAIP3 pool
CC intact. {ECO:0000269|PubMed:18223652, ECO:0000269|PubMed:20804738}.
CC -!- DISEASE: Autoinflammatory syndrome, familial, Behcet-like (AISBL)
CC [MIM:616744]: An autosomal dominant, autoinflammatory disorder with
CC early onset, characterized by ulceration of mucosal surfaces,
CC particularly in the oral and genital areas. Additional variable
CC features include skin rash, uveitis, and polyarthritis.
CC {ECO:0000269|PubMed:26642243, ECO:0000269|PubMed:27175295}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the peptidase C64 family. {ECO:0000305}.
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 and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/TNFAIP3ID42600ch6q23.html";
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DR EMBL; M59465; AAA51550.1; -; mRNA.
DR EMBL; AK312862; BAG35714.1; -; mRNA.
DR EMBL; AY248754; AAO61093.1; -; Genomic_DNA.
DR EMBL; AL357060; -; NOT_ANNOTATED_CDS; 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 CCDS; CCDS5187.1; -.
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 RefSeq; XP_005267176.1; XM_005267119.1.
DR RefSeq; XP_011534397.1; XM_011536095.1.
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 PDB; 5LRX; X-ray; 2.85 A; A/C/E/F=1-366.
DR PDB; 5V3B; X-ray; 3.00 A; A/B/C/D/E/F=1-366.
DR PDB; 5V3P; X-ray; 2.50 A; A/B/C/D/E/F=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 PDBsum; 5LRX; -.
DR PDBsum; 5V3B; -.
DR PDBsum; 5V3P; -.
DR AlphaFoldDB; P21580; -.
DR SMR; P21580; -.
DR BioGRID; 112983; 162.
DR DIP; DIP-33804N; -.
DR IntAct; P21580; 76.
DR MINT; P21580; -.
DR STRING; 9606.ENSP00000481570; -.
DR ChEMBL; CHEMBL4523200; -.
DR MEROPS; C64.003; -.
DR GlyGen; P21580; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; P21580; -.
DR PhosphoSitePlus; P21580; -.
DR BioMuta; TNFAIP3; -.
DR DMDM; 112894; -.
DR EPD; P21580; -.
DR jPOST; P21580; -.
DR MassIVE; P21580; -.
DR MaxQB; P21580; -.
DR PaxDb; P21580; -.
DR PeptideAtlas; P21580; -.
DR PRIDE; P21580; -.
DR ProteomicsDB; 53879; -.
DR Antibodypedia; 1049; 513 antibodies from 45 providers.
DR DNASU; 7128; -.
DR Ensembl; ENST00000237289.8; ENSP00000237289.4; ENSG00000118503.16.
DR Ensembl; ENST00000612899.5; ENSP00000481570.1; ENSG00000118503.16.
DR GeneID; 7128; -.
DR KEGG; hsa:7128; -.
DR MANE-Select; ENST00000612899.5; ENSP00000481570.1; NM_001270508.2; NP_001257437.1.
DR UCSC; uc003qhr.5; human.
DR CTD; 7128; -.
DR DisGeNET; 7128; -.
DR GeneCards; TNFAIP3; -.
DR HGNC; HGNC:11896; TNFAIP3.
DR HPA; ENSG00000118503; Tissue enhanced (bone).
DR MalaCards; TNFAIP3; -.
DR MIM; 191163; gene.
DR MIM; 616744; phenotype.
DR neXtProt; NX_P21580; -.
DR OpenTargets; ENSG00000118503; -.
DR Orphanet; 476102; Hereditary pediatric Behcet-like disease.
DR Orphanet; 536; Systemic lupus erythematosus.
DR PharmGKB; PA36593; -.
DR VEuPathDB; HostDB:ENSG00000118503; -.
DR eggNOG; KOG4345; Eukaryota.
DR GeneTree; ENSGT00940000158448; -.
DR HOGENOM; CLU_019606_0_0_1; -.
DR InParanoid; P21580; -.
DR OMA; QFKQLYG; -.
DR OrthoDB; 728724at2759; -.
DR PhylomeDB; P21580; -.
DR TreeFam; TF323312; -.
DR PathwayCommons; P21580; -.
DR Reactome; R-HSA-168638; NOD1/2 Signaling Pathway.
DR Reactome; R-HSA-5357786; TNFR1-induced proapoptotic signaling.
DR Reactome; R-HSA-5357905; Regulation of TNFR1 signaling.
DR Reactome; R-HSA-5357956; TNFR1-induced NFkappaB signaling pathway.
DR Reactome; R-HSA-5689896; Ovarian tumor domain proteases.
DR Reactome; R-HSA-936440; Negative regulators of DDX58/IFIH1 signaling.
DR SignaLink; P21580; -.
DR SIGNOR; P21580; -.
DR BioGRID-ORCS; 7128; 26 hits in 1129 CRISPR screens.
DR ChiTaRS; TNFAIP3; human.
DR EvolutionaryTrace; P21580; -.
DR GeneWiki; TNFAIP3; -.
DR GenomeRNAi; 7128; -.
DR Pharos; P21580; Tbio.
DR PRO; PR:P21580; -.
DR Proteomes; UP000005640; Chromosome 6.
DR RNAct; P21580; protein.
DR Bgee; ENSG00000118503; Expressed in vena cava and 189 other tissues.
DR ExpressionAtlas; P21580; baseline and differential.
DR Genevisible; P21580; HS.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR GO; GO:0005764; C:lysosome; IEA:UniProtKB-SubCell.
DR GO; GO:0005634; C:nucleus; IDA:HGNC-UCL.
DR GO; GO:0004843; F:cysteine-type deubiquitinase activity; IDA:UniProtKB.
DR GO; GO:0003677; F:DNA binding; IEA:UniProtKB-KW.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0070530; F:K63-linked polyubiquitin modification-dependent protein binding; IBA:GO_Central.
DR GO; GO:0019900; F:kinase binding; IEA:Ensembl.
DR GO; GO:0061578; F:Lys63-specific deubiquitinase activity; EXP:Reactome.
DR GO; GO:0002020; F:protease binding; IPI:BHF-UCL.
DR GO; GO:0008022; F:protein C-terminus binding; IEA:Ensembl.
DR GO; GO:0043621; F:protein self-association; IDA:BHF-UCL.
DR GO; GO:0043130; F:ubiquitin binding; IPI:BHF-UCL.
DR GO; GO:0004842; F:ubiquitin-protein transferase activity; IDA:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0001922; P:B-1 B cell homeostasis; ISS:BHF-UCL.
DR GO; GO:0016477; P:cell migration; IBA:GO_Central.
DR GO; GO:0070301; P:cellular response to hydrogen peroxide; ISS:UniProtKB.
DR GO; GO:0071222; P:cellular response to lipopolysaccharide; IDA:BHF-UCL.
DR GO; GO:0007010; P:cytoskeleton organization; IBA:GO_Central.
DR GO; GO:0072666; P:establishment of protein localization to vacuole; IEA:Ensembl.
DR GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW.
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:Ensembl.
DR GO; GO:0045736; P:negative regulation of cyclin-dependent protein serine/threonine kinase activity; IEA:Ensembl.
DR GO; GO:2000352; P:negative regulation of endothelial cell apoptotic process; IDA:BHF-UCL.
DR GO; GO:1902042; P:negative regulation of extrinsic apoptotic signaling pathway via death domain receptors; IDA:BHF-UCL.
DR GO; GO:0043124; P:negative regulation of I-kappaB kinase/NF-kappaB signaling; 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; IMP:MGI.
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:Ensembl.
DR GO; GO:0070433; P:negative regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway; IEA:Ensembl.
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:0034144; P:negative regulation of toll-like receptor 4 signaling pathway; NAS:BHF-UCL.
DR GO; GO:0034148; P:negative regulation of toll-like receptor 5 signaling pathway; IEA:Ensembl.
DR GO; GO:0032720; P:negative regulation of tumor necrosis factor production; ISS:BHF-UCL.
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:Ensembl.
DR GO; GO:0045732; P:positive regulation of protein catabolic process; IDA:BHF-UCL.
DR GO; GO:0030177; P:positive regulation of Wnt signaling pathway; IBA:GO_Central.
DR GO; GO:0016579; P:protein deubiquitination; TAS:BHF-UCL.
DR GO; GO:0071947; P:protein deubiquitination involved in ubiquitin-dependent protein catabolic process; IBA:GO_Central.
DR GO; GO:0035871; P:protein K11-linked deubiquitination; IDA:UniProtKB.
DR GO; GO:0035523; P:protein K29-linked deubiquitination; IBA:GO_Central.
DR GO; GO:1990168; P:protein K33-linked deubiquitination; IBA:GO_Central.
DR GO; GO:0071108; P:protein K48-linked deubiquitination; IDA:UniProtKB.
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: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:0010803; P:regulation of tumor necrosis factor-mediated signaling pathway; TAS:Reactome.
DR GO; GO:0061043; P:regulation of vascular wound healing; NAS:BHF-UCL.
DR GO; GO:0002237; P:response to molecule of bacterial origin; IDA:BHF-UCL.
DR GO; GO:0032495; P:response to muramyl dipeptide; IEA:Ensembl.
DR GO; GO:0072573; P:tolerance induction to lipopolysaccharide; IMP:BHF-UCL.
DR InterPro; IPR033478; A20.
DR InterPro; IPR003323; OTU_dom.
DR InterPro; IPR002653; Znf_A20.
DR PANTHER; PTHR13367:SF3; PTHR13367:SF3; 1.
DR Pfam; PF02338; OTU; 1.
DR Pfam; PF01754; zf-A20; 4.
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; Acetylation; Apoptosis; Cytoplasm; Disease variant;
KW DNA-binding; Hydrolase; Inflammatory response; Lysosome; Metal-binding;
KW Multifunctional enzyme; Nucleus; Phosphoprotein; Protease;
KW Reference proteome; Repeat; Thiol protease; Transferase;
KW Ubl conjugation pathway; Zinc; Zinc-finger.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0007744|PubMed:22814378"
FT CHAIN 2..790
FT /note="Tumor necrosis factor alpha-induced protein 3"
FT /id="PRO_0000188791"
FT CHAIN 2..439
FT /note="A20p50"
FT /id="PRO_0000418127"
FT CHAIN 440..790
FT /note="A20p37"
FT /id="PRO_0000418128"
FT DOMAIN 92..263
FT /note="OTU"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00139"
FT ZN_FING 381..416
FT /note="A20-type 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT ZN_FING 472..507
FT /note="A20-type 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT ZN_FING 515..548
FT /note="A20-type 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT ZN_FING 601..636
FT /note="A20-type 4"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT ZN_FING 651..686
FT /note="A20-type 5"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT ZN_FING 710..745
FT /note="A20-type 6"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT ZN_FING 756..790
FT /note="A20-type 7"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT REGION 58..300
FT /note="TRAF-binding"
FT REGION 157..159
FT /note="Interaction with ubiquitin"
FT /evidence="ECO:0000305"
FT REGION 190..192
FT /note="Interaction with ubiquitin"
FT /evidence="ECO:0000305"
FT REGION 224..227
FT /note="Interaction with ubiquitin"
FT /evidence="ECO:0000305"
FT REGION 357..377
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 369..775
FT /note="Interaction with TNIP1"
FT /evidence="ECO:0000250"
FT REGION 386..453
FT /note="Interaction with RIPK1"
FT /evidence="ECO:0000269|PubMed:19131965"
FT REGION 415..434
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 447..468
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 550..583
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 605..655
FT /note="Required for proteosomal degradation of UBE2N and
FT UBE2D3, TRAF6 deubiquitination, and TAX1BP1 interaction
FT with UBE2N"
FT /evidence="ECO:0000250"
FT REGION 606..790
FT /note="Sufficient for inhibitory activity of TNF-induced
FT NF-kappa-B activity"
FT /evidence="ECO:0000250"
FT REGION 689..712
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 697..790
FT /note="Required for lysosomal localization and for TRAF2
FT lysosomal degradation"
FT COMPBIAS 550..572
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 100
FT /evidence="ECO:0000250"
FT ACT_SITE 103
FT /note="Nucleophile"
FT /evidence="ECO:0000269|PubMed:18164316"
FT ACT_SITE 256
FT /note="Proton acceptor"
FT /evidence="ECO:0000305|PubMed:18164316"
FT BINDING 387
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 392
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 404
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 407
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 478
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 483
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 495
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 498
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 521
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 524
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 536
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 539
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 607
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="4"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 612
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="4"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 624
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="4"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 627
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="4"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 657
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="5"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 662
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="5"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 674
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="5"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 677
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="5"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 716
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="6"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 721
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="6"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 733
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="6"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 736
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="6"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 762
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="7"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 767
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="7"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 779
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="7"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT BINDING 782
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="7"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00451"
FT SITE 439..440
FT /note="Cleavage; by MALT1"
FT MOD_RES 2
FT /note="N-acetylalanine"
FT /evidence="ECO:0007744|PubMed:22814378"
FT MOD_RES 459
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:19690332"
FT MOD_RES 575
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:24275569"
FT MOD_RES 645
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT VARIANT 125
FT /note="A -> V (in dbSNP:rs5029941)"
FT /evidence="ECO:0000269|Ref.3"
FT /id="VAR_020447"
FT VARIANT 127
FT /note="F -> C (in dbSNP:rs2230926)"
FT /evidence="ECO:0000269|Ref.3"
FT /id="VAR_022143"
FT VARIANT 243
FT /note="C -> Y (in AISBL; increases inflammatory cytokine
FT secretion; increases NF-kappaB signaling)"
FT /evidence="ECO:0000269|PubMed:27175295"
FT /id="VAR_076302"
FT VARIANT 766
FT /note="A -> P (in dbSNP:rs5029957)"
FT /evidence="ECO:0000269|Ref.3"
FT /id="VAR_029319"
FT MUTAGEN 70
FT /note="D->A: Minor effect on 'Lys-48' deubiquitinase
FT activity. Strongly reduced 'Lys-63' deubiquitinase
FT activity."
FT /evidence="ECO:0000269|PubMed:17961127,
FT ECO:0000269|PubMed:18164316"
FT MUTAGEN 97
FT /note="T->A: Minor effect on 'Lys-48' deubiquitinase
FT activity."
FT /evidence="ECO:0000269|PubMed:18164316"
FT MUTAGEN 100
FT /note="D->A: Strongly reduced deubiquitinase activity."
FT /evidence="ECO:0000269|PubMed:18164316"
FT MUTAGEN 103
FT /note="C->A: Loss of deubiquitinase activity."
FT /evidence="ECO:0000269|PubMed:14748687,
FT ECO:0000269|PubMed:15258597, ECO:0000269|PubMed:17961127,
FT ECO:0000269|PubMed:18164316"
FT MUTAGEN 103
FT /note="C->S: Loss of 'Lys-63' deubiquitinating activity.
FT Down-regulation of TNF-induced NF-kappa-B activity less
FT effective."
FT /evidence="ECO:0000269|PubMed:14748687,
FT ECO:0000269|PubMed:15258597, ECO:0000269|PubMed:17961127,
FT ECO:0000269|PubMed:18164316"
FT MUTAGEN 106
FT /note="H->A: Reduces deubiquitinase activity."
FT /evidence="ECO:0000269|PubMed:27732584"
FT MUTAGEN 157
FT /note="L->A: Strongly reduced 'Lys-48' deubiquitinase
FT activity."
FT /evidence="ECO:0000269|PubMed:18164316"
FT MUTAGEN 159
FT /note="Y->A: Strongly reduced 'Lys-48' deubiquitinase
FT activity."
FT /evidence="ECO:0000269|PubMed:18164316"
FT MUTAGEN 190
FT /note="S->A: Strongly reduced 'Lys-48' deubiquitinase
FT activity."
FT /evidence="ECO:0000269|PubMed:18164316"
FT MUTAGEN 192
FT /note="E->A: Strongly reduced 'Lys-48' deubiquitinase
FT activity."
FT /evidence="ECO:0000269|PubMed:18164316"
FT MUTAGEN 224
FT /note="F->A: Strongly reduced 'Lys-48' deubiquitinase
FT activity."
FT /evidence="ECO:0000269|PubMed:18164316"
FT MUTAGEN 227
FT /note="L->A: Strongly reduced 'Lys-48' deubiquitinase
FT activity."
FT /evidence="ECO:0000269|PubMed:18164316"
FT MUTAGEN 256
FT /note="H->A: Loss of deubiquitinase activity."
FT /evidence="ECO:0000269|PubMed:17961127,
FT ECO:0000269|PubMed:27732584"
FT MUTAGEN 521
FT /note="C->A: No effect on ubiquitin ligase activity; when
FT associated with A-524."
FT /evidence="ECO:0000269|PubMed:15258597"
FT MUTAGEN 524
FT /note="C->A: No effect on ubiquitin ligase activity; when
FT associated with A-521."
FT /evidence="ECO:0000269|PubMed:15258597"
FT MUTAGEN 562
FT /note="R->A: Abolishes interactionj with YWHAZ AND YWHAH;
FT no effect on inhibitory activity of TNF-induced NF-kappa-B
FT activation."
FT /evidence="ECO:0000269|PubMed:9299557"
FT MUTAGEN 565
FT /note="S->A: Abolishes interactionj with YWHAZ AND YWHAH;
FT no effect on inhibitory activity of TNF-induced NF-kappa-B
FT activation."
FT /evidence="ECO:0000269|PubMed:9299557"
FT MUTAGEN 614
FT /note="Y->A: Impairs ubiquitination activity. Loss of down-
FT regulation of NF-kappa-B activity; when associated with A-
FT 615 or R-626."
FT /evidence="ECO:0000269|PubMed:21095585"
FT MUTAGEN 615
FT /note="F->A: Impairs ubiquitination activity. Loss of down-
FT regulation of NF-kappa-B activity; when associated with A-
FT 614."
FT /evidence="ECO:0000269|PubMed:21095585"
FT MUTAGEN 624
FT /note="C->A: Marked attenuation of ubiquitin ligase
FT activity and inhibition of RIPK1 degradation; when
FT associated with A-627."
FT /evidence="ECO:0000269|PubMed:15258597"
FT MUTAGEN 626
FT /note="L->R: Impairs ubiquitination activity. Loss of down-
FT regulation of NF-kappa-B activity; when associated with A-
FT 614."
FT /evidence="ECO:0000269|PubMed:21095585"
FT MUTAGEN 627
FT /note="C->A: Marked attenuation of ubiquitin ligase
FT activity and inhibition of RIPK1 degradation; when
FT associated with A-624."
FT /evidence="ECO:0000269|PubMed:15258597"
FT MUTAGEN 770..771
FT /note="FG->AA: Impairs polyubiquitin binding, abolishes
FT inhibition of IKK activation."
FT /evidence="ECO:0000269|PubMed:22099304"
FT MUTAGEN 779
FT /note="C->A: Impairs polyubiquitin binding, abolishes
FT inhibition of IKK activation; when associated with A-782."
FT /evidence="ECO:0000269|PubMed:22099304"
FT MUTAGEN 782
FT /note="C->A: Impairs polyubiquitin binding, abolishes
FT inhibition of IKK activation; when associated with A-779."
FT /evidence="ECO:0000269|PubMed:22099304"
FT HELIX 10..13
FT /evidence="ECO:0007829|PDB:3ZJE"
FT HELIX 15..27
FT /evidence="ECO:0007829|PDB:3ZJE"
FT STRAND 33..35
FT /evidence="ECO:0007829|PDB:3ZJE"
FT STRAND 39..42
FT /evidence="ECO:0007829|PDB:3ZJE"
FT HELIX 43..45
FT /evidence="ECO:0007829|PDB:3ZJE"
FT STRAND 54..56
FT /evidence="ECO:0007829|PDB:3ZJG"
FT HELIX 58..68
FT /evidence="ECO:0007829|PDB:3ZJE"
FT HELIX 71..79
FT /evidence="ECO:0007829|PDB:3ZJE"
FT STRAND 82..84
FT /evidence="ECO:0007829|PDB:3ZJG"
FT STRAND 87..89
FT /evidence="ECO:0007829|PDB:3DKB"
FT STRAND 92..95
FT /evidence="ECO:0007829|PDB:3ZJE"
FT HELIX 103..113
FT /evidence="ECO:0007829|PDB:3ZJE"
FT HELIX 121..132
FT /evidence="ECO:0007829|PDB:3ZJE"
FT HELIX 136..147
FT /evidence="ECO:0007829|PDB:3ZJE"
FT HELIX 152..155
FT /evidence="ECO:0007829|PDB:5LRX"
FT HELIX 164..174
FT /evidence="ECO:0007829|PDB:3ZJE"
FT STRAND 176..178
FT /evidence="ECO:0007829|PDB:5LRX"
FT STRAND 181..185
FT /evidence="ECO:0007829|PDB:3DKB"
FT HELIX 193..203
FT /evidence="ECO:0007829|PDB:3ZJE"
FT STRAND 207..211
FT /evidence="ECO:0007829|PDB:3ZJE"
FT STRAND 213..216
FT /evidence="ECO:0007829|PDB:5LRX"
FT TURN 218..220
FT /evidence="ECO:0007829|PDB:5LRX"
FT STRAND 221..226
FT /evidence="ECO:0007829|PDB:5LRX"
FT STRAND 231..233
FT /evidence="ECO:0007829|PDB:3ZJE"
FT HELIX 240..242
FT /evidence="ECO:0007829|PDB:3ZJE"
FT STRAND 248..253
FT /evidence="ECO:0007829|PDB:3ZJE"
FT STRAND 256..263
FT /evidence="ECO:0007829|PDB:3ZJE"
FT STRAND 267..270
FT /evidence="ECO:0007829|PDB:3ZJG"
FT STRAND 272..279
FT /evidence="ECO:0007829|PDB:3ZJE"
FT STRAND 282..285
FT /evidence="ECO:0007829|PDB:3ZJE"
FT HELIX 293..297
FT /evidence="ECO:0007829|PDB:3ZJE"
FT HELIX 299..306
FT /evidence="ECO:0007829|PDB:3ZJE"
FT STRAND 309..315
FT /evidence="ECO:0007829|PDB:3ZJE"
FT STRAND 317..329
FT /evidence="ECO:0007829|PDB:3ZJE"
FT HELIX 337..339
FT /evidence="ECO:0007829|PDB:3ZJE"
FT HELIX 341..354
FT /evidence="ECO:0007829|PDB:3ZJE"
FT HELIX 359..361
FT /evidence="ECO:0007829|PDB:3DKB"
FT STRAND 384..386
FT /evidence="ECO:0007829|PDB:2EQG"
FT TURN 398..402
FT /evidence="ECO:0007829|PDB:2EQG"
FT HELIX 405..412
FT /evidence="ECO:0007829|PDB:2EQG"
FT STRAND 604..606
FT /evidence="ECO:0007829|PDB:2EQE"
FT STRAND 613..615
FT /evidence="ECO:0007829|PDB:3OJ3"
FT HELIX 618..620
FT /evidence="ECO:0007829|PDB:3OJ3"
FT HELIX 625..634
FT /evidence="ECO:0007829|PDB:3OJ3"
FT HELIX 773..775
FT /evidence="ECO:0007829|PDB:3VUX"
FT HELIX 780..788
FT /evidence="ECO:0007829|PDB:3VUX"
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
