OTUD4_HUMAN
ID OTUD4_HUMAN Reviewed; 1114 AA.
AC Q01804; B4DYS4; Q147U2; Q1ZYK1; Q6PG39; Q96MQ5; Q9NT94; Q9UPV6;
DT 01-JUN-1994, integrated into UniProtKB/Swiss-Prot.
DT 19-MAR-2014, sequence version 4.
DT 03-AUG-2022, entry version 173.
DE RecName: Full=OTU domain-containing protein 4;
DE EC=3.4.19.12 {ECO:0000269|PubMed:23827681, ECO:0000269|PubMed:25944111, ECO:0000269|PubMed:29395066};
DE AltName: Full=HIV-1-induced protein HIN-1 {ECO:0000303|PubMed:1475186};
GN Name=OTUD4 {ECO:0000312|HGNC:HGNC:24949};
GN Synonyms=HIN-1 {ECO:0000303|PubMed:1475186},
GN KIAA1046 {ECO:0000303|PubMed:10470851};
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 [LARGE SCALE MRNA] (ISOFORM 3).
RC TISSUE=Testis, and Tongue;
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 [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
RA Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT 4.";
RL Nature 434:724-731(2005).
RN [3]
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 [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4), AND INDUCTION.
RX PubMed=1475186; DOI=10.1093/nar/20.23.6261;
RA Raineri I., Senn H.-P.;
RT "HIV-1 promotor insertion revealed by selective detection of chimeric
RT provirus-host gene transcripts.";
RL Nucleic Acids Res. 20:6261-6266(1992).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], ALTERNATIVE SPLICING (ISOFORM 2), AND
RP VARIANTS GLY-194 AND THR-216.
RG SeattleSNPs variation discovery resource;
RL Submitted (MAR-2006) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
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 [7]
RP PROTEIN SEQUENCE OF 1-19; 49-60; 250-266; 414-420; 436-447; 458-465;
RP 701-708; 917-936; 945-970 AND 1000-1015, ACETYLATION AT MET-1, AND
RP IDENTIFICATION BY MASS SPECTROMETRY.
RC TISSUE=Colon carcinoma, and Mammary carcinoma;
RA Bienvenut W.V., Heiserich L., Boulahbel H., Gottlieb E., Matallanas D.,
RA Cooper W.N., Kolch W.;
RL Submitted (JUL-2007) to UniProtKB.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 709-1114 (ISOFORMS 1/2/3).
RC TISSUE=Brain;
RX PubMed=10470851; DOI=10.1093/dnares/6.3.197;
RA Kikuno R., Nagase T., Ishikawa K., Hirosawa M., Miyajima N., Tanaka A.,
RA Kotani H., Nomura N., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. XIV. The
RT complete sequences of 100 new cDNA clones from brain which code for large
RT proteins in vitro.";
RL DNA Res. 6:197-205(1999).
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 815-1114 (ISOFORMS 1/2/3).
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 [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-460, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=15144186; DOI=10.1021/ac035352d;
RA Brill L.M., Salomon A.R., Ficarro S.B., Mukherji M., Stettler-Gill M.,
RA Peters E.C.;
RT "Robust phosphoproteomic profiling of tyrosine phosphorylation sites from
RT human T cells using immobilized metal affinity chromatography and tandem
RT mass spectrometry.";
RL Anal. Chem. 76:2763-2772(2004).
RN [11]
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 [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1006, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=16964243; DOI=10.1038/nbt1240;
RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
RT "A probability-based approach for high-throughput protein phosphorylation
RT analysis and site localization.";
RL Nat. Biotechnol. 24:1285-1292(2006).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-443; SER-1006; SER-1023 AND
RP SER-1024, AND 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 [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [15]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-443; SER-1006; SER-1023 AND
RP SER-1024, AND IDENTIFICATION BY 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 [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-893; SER-900; SER-1023 AND
RP SER-1024, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [17]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [18]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-893 AND SER-1006, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T.,
RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.;
RT "System-wide temporal characterization of the proteome and phosphoproteome
RT of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [19]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22223895; DOI=10.1074/mcp.m111.015131;
RA Bienvenut W.V., Sumpton D., Martinez A., Lilla S., Espagne C., Meinnel T.,
RA Giglione C.;
RT "Comparative large-scale characterisation of plant vs. mammal proteins
RT reveals similar and idiosyncratic N-alpha acetylation features.";
RL Mol. Cell. Proteomics 11:M111.015131-M111.015131(2012).
RN [20]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [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 [21]
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 [22]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-341; SER-443; SER-546;
RP SER-893; SER-1014; SER-1023; SER-1024 AND SER-1049, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and 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 [23]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-443, 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 [24]
RP VARIANT VAL-398.
RX PubMed=23656588; DOI=10.1056/nejmoa1215993;
RA Margolin D.H., Kousi M., Chan Y.M., Lim E.T., Schmahmann J.D.,
RA Hadjivassiliou M., Hall J.E., Adam I., Dwyer A., Plummer L., Aldrin S.V.,
RA O'Rourke J., Kirby A., Lage K., Milunsky A., Milunsky J.M., Chan J.,
RA Hedley-Whyte E.T., Daly M.J., Katsanis N., Seminara S.B.;
RT "Ataxia, dementia, and hypogonadotropism caused by disordered
RT ubiquitination.";
RL N. Engl. J. Med. 368:1992-2003(2013).
RN [25]
RP FUNCTION, CATALYTIC ACTIVITY, INTERACTION WITH ALKBH3; USP7 AND USP9X,
RP SUBCELLULAR LOCATION, ACTIVE SITE, AND MUTAGENESIS OF CYS-45 AND
RP 181-VAL--SER-550.
RX PubMed=25944111; DOI=10.15252/embj.201490497;
RA Zhao Y., Majid M.C., Soll J.M., Brickner J.R., Dango S., Mosammaparast N.;
RT "Noncanonical regulation of alkylation damage resistance by the OTUD4
RT deubiquitinase.";
RL EMBO J. 34:1687-1703(2015).
RN [26]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, INTERACTION WITH MYD88,
RP PHOSPHORYLATION AT TYR-120; SER-126; SER-128; THR-131; SER-166; SER-199;
RP SER-202 AND SER-204, IDENTIFICATION BY MASS SPECTROMETRY, ACTIVE SITE, AND
RP MUTAGENESIS OF CYS-45; SER-202; SER-204; 273-LYS--ASP-275 AND ALA-279.
RX PubMed=29395066; DOI=10.1016/j.molcel.2018.01.009;
RA Zhao Y., Mudge M.C., Soll J.M., Rodrigues R.B., Byrum A.K.,
RA Schwarzkopf E.A., Bradstreet T.R., Gygi S.P., Edelson B.T.,
RA Mosammaparast N.;
RT "OTUD4 Is a Phospho-Activated K63 Deubiquitinase that Regulates MyD88-
RT Dependent Signaling.";
RL Mol. Cell 69:505-516(2018).
CC -!- FUNCTION: Deubiquitinase which hydrolyzes the isopeptide bond between
CC the ubiquitin C-terminus and the lysine epsilon-amino group of the
CC target protein (PubMed:23827681, PubMed:25944111, PubMed:29395066). May
CC negatively regulate inflammatory and pathogen recognition signaling in
CC innate immune response. Upon phosphorylation at Ser-202 and Ser-204
CC residues, via IL-1 receptor and Toll-like receptor signaling pathway,
CC specifically deubiquitinates 'Lys-63'-polyubiquitinated MYD88 adapter
CC protein triggering down-regulation of NF-kappa-B-dependent
CC transcription of inflammatory mediators (PubMed:29395066).
CC Independently of the catalytic activity, acts as a scaffold for
CC alternative deubiquitinases to assemble specific deubiquitinase-
CC substrate complexes. Associates with USP7 and USP9X deubiquitinases to
CC stabilize alkylation repair enzyme ALKBH3, thereby promoting the repair
CC of alkylated DNA lesions (PubMed:25944111).
CC {ECO:0000269|PubMed:23827681, ECO:0000269|PubMed:25944111,
CC ECO:0000269|PubMed:29395066}.
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:23827681,
CC ECO:0000269|PubMed:25944111, ECO:0000269|PubMed:29395066};
CC -!- ACTIVITY REGULATION: Phosphorylation on Ser-202 and Ser-204 induces
CC 'Lys-63'-specific deubiquitinase activity.
CC {ECO:0000269|PubMed:29395066}.
CC -!- SUBUNIT: Interacts with MYD88; the interaction is direct
CC (PubMed:29395066). Interacts with ALKBH3; the interaction is direct
CC (PubMed:25944111). Interacts with USP7; the interaction is direct
CC (PubMed:25944111). Interacts with USP9X; the interaction is direct
CC (PubMed:25944111). {ECO:0000269|PubMed:25944111,
CC ECO:0000269|PubMed:29395066}.
CC -!- INTERACTION:
CC Q01804; Q96B26: EXOSC8; NbExp=6; IntAct=EBI-1054396, EBI-371922;
CC Q01804; Q04864: REL; NbExp=3; IntAct=EBI-1054396, EBI-307352;
CC Q01804; P42224: STAT1; NbExp=3; IntAct=EBI-1054396, EBI-1057697;
CC Q01804; P15884: TCF4; NbExp=3; IntAct=EBI-1054396, EBI-533224;
CC Q01804; P11473-2: VDR; NbExp=3; IntAct=EBI-1054396, EBI-12874016;
CC Q01804; Q8N720: ZNF655; NbExp=3; IntAct=EBI-1054396, EBI-625509;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:25944111}. Nucleus
CC {ECO:0000269|PubMed:25944111}. Note=Primarily cytoplasmic.
CC {ECO:0000269|PubMed:25944111}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1;
CC IsoId=Q01804-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q01804-5; Sequence=VSP_038830, VSP_053825;
CC Name=3;
CC IsoId=Q01804-3; Sequence=VSP_038830;
CC Name=4;
CC IsoId=Q01804-4; Sequence=VSP_038830, VSP_021671;
CC -!- INDUCTION: By HIV-1 insertion. {ECO:0000269|PubMed:1475186}.
CC -!- PTM: Phosphorylated on Ser-202 and Ser-204 likely by CSNK2A1-CSNK2A2
CC serine/threonine-protein kinase complex. Activates 'Lys-63'-specific
CC deubiquitinase activity. {ECO:0000269|PubMed:29395066}.
CC -!- MISCELLANEOUS: [Isoform 4]: Predicted from a chimeric transcript
CC isolated from HIV-1-infected cells. The premature stop may be due to
CC intron retention. {ECO:0000305}.
CC -!- CAUTION: When expressed in bacteria, recombinant OTUD4 specifically
CC hydrolyzes 'Lys-48'-linked diubiquitin. The physiological relevance of
CC this activity remains unknown (PubMed:23827681, PubMed:25944111,
CC PubMed:29395066). In vivo deubiquitinates 'Lys-63'-linked ubiquitin
CC chains (PubMed:29395066). {ECO:0000269|PubMed:23827681,
CC ECO:0000269|PubMed:25944111, ECO:0000269|PubMed:29395066}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH57242.2; Type=Miscellaneous discrepancy; Note=Sequence of unknown origin in the N-terminal part.; Evidence={ECO:0000305};
CC Sequence=BAA82998.2; Type=Miscellaneous discrepancy; Note=Intron retention.; Evidence={ECO:0000305};
CC Sequence=BAB71229.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/otud4/";
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DR EMBL; AK056597; BAB71229.1; ALT_INIT; mRNA.
DR EMBL; AK302581; BAG63836.1; -; mRNA.
DR EMBL; AC096757; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471056; EAX05045.1; -; Genomic_DNA.
DR EMBL; CH471056; EAX05046.1; -; Genomic_DNA.
DR EMBL; X68242; CAA48313.1; -; mRNA.
DR EMBL; DQ427109; ABD72605.1; -; Genomic_DNA.
DR EMBL; BC057242; AAH57242.2; ALT_SEQ; mRNA.
DR EMBL; BC118572; AAI18573.1; -; mRNA.
DR EMBL; BC118653; AAI18654.1; -; mRNA.
DR EMBL; AB028969; BAA82998.2; ALT_SEQ; mRNA.
DR EMBL; AL137460; CAB70748.1; -; mRNA.
DR CCDS; CCDS3764.1; -. [Q01804-4]
DR CCDS; CCDS47139.1; -. [Q01804-3]
DR PIR; S30247; S30247.
DR PIR; T46403; T46403.
DR RefSeq; NP_001096123.1; NM_001102653.1. [Q01804-3]
DR RefSeq; NP_059963.1; NM_017493.6. [Q01804-4]
DR RefSeq; XP_005263136.1; XM_005263079.4.
DR AlphaFoldDB; Q01804; -.
DR SMR; Q01804; -.
DR BioGRID; 120112; 664.
DR IntAct; Q01804; 62.
DR MINT; Q01804; -.
DR STRING; 9606.ENSP00000409279; -.
DR MEROPS; C85.P01; -.
DR GlyGen; Q01804; 5 sites, 1 O-linked glycan (5 sites).
DR iPTMnet; Q01804; -.
DR PhosphoSitePlus; Q01804; -.
DR BioMuta; OTUD4; -.
DR DMDM; 302393819; -.
DR EPD; Q01804; -.
DR jPOST; Q01804; -.
DR MassIVE; Q01804; -.
DR MaxQB; Q01804; -.
DR PaxDb; Q01804; -.
DR PeptideAtlas; Q01804; -.
DR PRIDE; Q01804; -.
DR ProteomicsDB; 57988; -. [Q01804-1]
DR ProteomicsDB; 57990; -. [Q01804-3]
DR ProteomicsDB; 57991; -. [Q01804-4]
DR Antibodypedia; 27452; 194 antibodies from 32 providers.
DR DNASU; 54726; -.
DR Ensembl; ENST00000447906.8; ENSP00000395487.2; ENSG00000164164.17. [Q01804-1]
DR Ensembl; ENST00000454497.6; ENSP00000409279.2; ENSG00000164164.17. [Q01804-3]
DR Ensembl; ENST00000509620.6; ENSP00000424192.2; ENSG00000164164.17. [Q01804-4]
DR GeneID; 54726; -.
DR KEGG; hsa:54726; -.
DR MANE-Select; ENST00000447906.8; ENSP00000395487.2; NM_001366057.1; NP_001352986.1.
DR UCSC; uc003ika.5; human. [Q01804-1]
DR CTD; 54726; -.
DR DisGeNET; 54726; -.
DR GeneCards; OTUD4; -.
DR HGNC; HGNC:24949; OTUD4.
DR HPA; ENSG00000164164; Low tissue specificity.
DR MIM; 611744; gene.
DR neXtProt; NX_Q01804; -.
DR OpenTargets; ENSG00000164164; -.
DR PharmGKB; PA142671216; -.
DR VEuPathDB; HostDB:ENSG00000164164; -.
DR eggNOG; KOG2605; Eukaryota.
DR GeneTree; ENSGT00940000160512; -.
DR HOGENOM; CLU_291170_0_0_1; -.
DR InParanoid; Q01804; -.
DR OMA; IYREPNA; -.
DR OrthoDB; 222767at2759; -.
DR PhylomeDB; Q01804; -.
DR TreeFam; TF326812; -.
DR PathwayCommons; Q01804; -.
DR SignaLink; Q01804; -.
DR BioGRID-ORCS; 54726; 35 hits in 1116 CRISPR screens.
DR ChiTaRS; OTUD4; human.
DR GeneWiki; OTUD4; -.
DR GenomeRNAi; 54726; -.
DR Pharos; Q01804; Tbio.
DR PRO; PR:Q01804; -.
DR Proteomes; UP000005640; Chromosome 4.
DR RNAct; Q01804; protein.
DR Bgee; ENSG00000164164; Expressed in middle frontal gyrus and 210 other tissues.
DR ExpressionAtlas; Q01804; baseline and differential.
DR Genevisible; Q01804; HS.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0004843; F:cysteine-type deubiquitinase activity; IDA:UniProtKB.
DR GO; GO:0061578; F:Lys63-specific deubiquitinase activity; IDA:UniProtKB.
DR GO; GO:0060090; F:molecular adaptor activity; IDA:UniProtKB.
DR GO; GO:0003723; F:RNA binding; HDA:UniProtKB.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:2000660; P:negative regulation of interleukin-1-mediated signaling pathway; IDA:UniProtKB.
DR GO; GO:0034122; P:negative regulation of toll-like receptor signaling pathway; IDA:UniProtKB.
DR GO; GO:1901537; P:positive regulation of DNA demethylation; IDA:UniProtKB.
DR GO; GO:0016579; P:protein deubiquitination; IBA:GO_Central.
DR GO; GO:0071108; P:protein K48-linked deubiquitination; IDA:UniProtKB.
DR GO; GO:0070536; P:protein K63-linked deubiquitination; IDA:UniProtKB.
DR GO; GO:1903093; P:regulation of protein K48-linked deubiquitination; IDA:UniProtKB.
DR InterPro; IPR003323; OTU_dom.
DR InterPro; IPR038765; Papain-like_cys_pep_sf.
DR Pfam; PF02338; OTU; 1.
DR SUPFAM; SSF54001; SSF54001; 1.
DR PROSITE; PS50802; OTU; 1.
PE 1: Evidence at protein level;
KW Acetylation; Alternative splicing; Cytoplasm; Direct protein sequencing;
KW Hydrolase; Immunity; Innate immunity; Nucleus; Phosphoprotein; Protease;
KW Reference proteome; Thiol protease; Ubl conjugation pathway.
FT CHAIN 1..1114
FT /note="OTU domain-containing protein 4"
FT /id="PRO_0000083979"
FT DOMAIN 34..155
FT /note="OTU"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00139,
FT ECO:0000269|PubMed:29395066"
FT REGION 1..22
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 39..45
FT /note="Cys-loop"
FT /evidence="ECO:0000250|UniProtKB:Q5VVQ6"
FT REGION 94..104
FT /note="Variable-loop"
FT /evidence="ECO:0000250|UniProtKB:Q5VVQ6"
FT REGION 143..148
FT /note="His-loop"
FT /evidence="ECO:0000250|UniProtKB:Q5VVQ6"
FT REGION 323..449
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 472..567
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 911..1114
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 342..357
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 387..417
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 418..449
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 472..493
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 494..534
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 536..552
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 973..1000
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1015..1033
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1034..1052
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1072..1114
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 42
FT /evidence="ECO:0000250|UniProtKB:Q96FW1"
FT ACT_SITE 45
FT /note="Nucleophile"
FT /evidence="ECO:0000269|PubMed:23827681,
FT ECO:0000269|PubMed:25944111, ECO:0000269|PubMed:29395066"
FT ACT_SITE 148
FT /evidence="ECO:0000250|UniProtKB:Q5VVQ6"
FT MOD_RES 1
FT /note="N-acetylmethionine"
FT /evidence="ECO:0000269|Ref.7, ECO:0007744|PubMed:22223895,
FT ECO:0007744|PubMed:22814378"
FT MOD_RES 120
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000269|PubMed:29395066"
FT MOD_RES 126
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:29395066"
FT MOD_RES 128
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:29395066"
FT MOD_RES 131
FT /note="Phosphothreonine"
FT /evidence="ECO:0000269|PubMed:29395066"
FT MOD_RES 166
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:29395066"
FT MOD_RES 199
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:29395066"
FT MOD_RES 202
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:29395066"
FT MOD_RES 204
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:29395066"
FT MOD_RES 341
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 439
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:B2RRE7"
FT MOD_RES 443
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:23186163,
FT ECO:0007744|PubMed:24275569"
FT MOD_RES 460
FT /note="Phosphotyrosine"
FT /evidence="ECO:0007744|PubMed:15144186"
FT MOD_RES 546
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 893
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:20068231,
FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163"
FT MOD_RES 900
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:20068231"
FT MOD_RES 1006
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:16964243,
FT ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:19690332,
FT ECO:0007744|PubMed:21406692"
FT MOD_RES 1011
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:B2RRE7"
FT MOD_RES 1014
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 1023
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:20068231,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 1024
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:20068231,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 1049
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT VAR_SEQ 1..65
FT /note="Missing (in isoform 2, isoform 3 and isoform 4)"
FT /evidence="ECO:0000303|PubMed:14702039,
FT ECO:0000303|PubMed:1475186, ECO:0000303|PubMed:15489334"
FT /id="VSP_038830"
FT VAR_SEQ 211..1114
FT /note="Missing (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:1475186"
FT /id="VSP_021671"
FT VAR_SEQ 231
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000305"
FT /id="VSP_053825"
FT VARIANT 194
FT /note="A -> G (in dbSNP:rs36225458)"
FT /evidence="ECO:0000269|Ref.5"
FT /id="VAR_029377"
FT VARIANT 216
FT /note="A -> T (in dbSNP:rs36225838)"
FT /evidence="ECO:0000269|Ref.5"
FT /id="VAR_038848"
FT VARIANT 398
FT /note="G -> V (could be associated with cerebellar ataxia
FT and hypogonadotropic hypogonadism; dbSNP:rs148857745)"
FT /evidence="ECO:0000269|PubMed:23656588"
FT /id="VAR_070050"
FT MUTAGEN 45
FT /note="C->A: Abolishes 'Lys-48'- and 'Lys-63'-specific
FT deubiquitinase activity. Impairs 'Lys-63'-specific
FT deubiquitinase activity toward MYD88 substrate."
FT /evidence="ECO:0000269|PubMed:23827681,
FT ECO:0000269|PubMed:25944111, ECO:0000269|PubMed:29395066"
FT MUTAGEN 45
FT /note="C->S: Abolishes 'Lys-48'- and 'Lys-63'-specific
FT deubiquitinase activity."
FT /evidence="ECO:0000269|PubMed:29395066"
FT MUTAGEN 181..550
FT /note="Missing: Abolishes interaction with USP7 and USP9X
FT deubiquitinases."
FT /evidence="ECO:0000269|PubMed:25944111"
FT MUTAGEN 202
FT /note="S->A: Decreases 'Lys-63'-specific deubiquitinase
FT activity. Loss of 'Lys-63'-specific deubiquitinase
FT activity; when associated with A-204."
FT /evidence="ECO:0000269|PubMed:29395066"
FT MUTAGEN 204
FT /note="S->A: Loss of 'Lys-63'-specific deubiquitinase
FT activity; when associated with A-204."
FT /evidence="ECO:0000269|PubMed:29395066"
FT MUTAGEN 273..275
FT /note="KRD->AAA: Abolishes 'Lys-63'-specific deubiquitinase
FT activity by impairing the affinity for 'Lys-63'-linked
FT ubiquitin chain substrate."
FT /evidence="ECO:0000269|PubMed:29395066"
FT MUTAGEN 279
FT /note="A->R: Abolishes 'Lys-63'-specific deubiquitinase
FT activity by impairing the affinity for 'Lys-63'-linked
FT ubiquitin chain substrate."
FT /evidence="ECO:0000269|PubMed:29395066"
FT CONFLICT 809
FT /note="S -> P (in Ref. 1; BAB71229)"
FT /evidence="ECO:0000305"
FT CONFLICT 915
FT /note="A -> S (in Ref. 9; CAB70748)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 1114 AA; 124045 MW; AD8DF5FEAB8CBE32 CRC64;
MEAAVGVPDG GDQGGAGPRE DATPMDAYLR KLGLYRKLVA KDGSCLFRAV AEQVLHSQSR
HVEVRMACIH YLRENREKFE AFIEGSFEEY LKRLENPQEW VGQVEISALS LMYRKDFIIY
REPNVSPSQV TENNFPEKVL LCFSNGNHYD IVYPIKYKES SAMCQSLLYE LLYEKVFKTD
VSKIVMELDT LEVADEDNSE ISDSEDDSCK SKTAAAAADV NGFKPLSGNE QLKNNGNSTS
LPLSRKVLKS LNPAVYRNVE YEIWLKSKQA QQKRDYSIAA GLQYEVGDKC QVRLDHNGKF
LNADVQGIHS ENGPVLVEEL GKKHTSKNLK APPPESWNTV SGKKMKKPST SGQNFHSDVD
YRGPKNPSKP IKAPSALPPR LQHPSGVRQH AFSSHSSGSQ SQKFSSEHKN LSRTPSQIIR
KPDRERVEDF DHTSRESNYF GLSPEERREK QAIEESRLLY EIQNRDEQAF PALSSSSVNQ
SASQSSNPCV QRKSSHVGDR KGSRRRMDTE ERKDKDSIHG HSQLDKRPEP STLENITDDK
YATVSSPSKS KKLECPSPAE QKPAEHVSLS NPAPLLVSPE VHLTPAVPSL PATVPAWPSE
PTTFGPTGVP APIPVLSVTQ TLTTGPDSAV SQAHLTPSPV PVSIQAVNQP LMPLPQTLSL
YQDPLYPGFP CNEKGDRAIV PPYSLCQTGE DLPKDKNILR FFFNLGVKAY SCPMWAPHSY
LYPLHQAYLA ACRMYPKVPV PVYPHNPWFQ EAPAAQNESD CTCTDAHFPM QTEASVNGQM
PQPEIGPPTF SSPLVIPPSQ VSESHGQLSY QADLESETPG QLLHADYEES LSGKNMFPQP
SFGPNPFLGP VPIAPPFFPH VWYGYPFQGF IENPVMRQNI VLPSDEKGEL DLSLENLDLS
KDCGSVSTVD EFPEARGEHV HSLPEASVSS KPDEGRTEQS SQTRKADTAL ASIPPVAEGK
AHPPTQILNR ERETVPVELE PKRTIQSLKE KTEKVKDPKT AADVVSPGAN SVDSRVQRPK
EESSEDENEV SNILRSGRSK QFYNQTYGSR KYKSDWGYSG RGGYQHVRSE ESWKGQPSRS
RDEGYQYHRN VRGRPFRGDR RRSGMGDGHR GQHT
