UBP4_HUMAN
ID UBP4_HUMAN Reviewed; 963 AA.
AC Q13107; A8K6Y0; C9IY91; O43452; O43453; Q08AK8;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 17-OCT-2006, sequence version 3.
DT 03-AUG-2022, entry version 197.
DE RecName: Full=Ubiquitin carboxyl-terminal hydrolase 4;
DE EC=3.4.19.12 {ECO:0000269|PubMed:16316627, ECO:0000269|PubMed:16339847, ECO:0000269|PubMed:16472766, ECO:0000269|PubMed:20595234, ECO:0000269|PubMed:22347420, ECO:0000269|PubMed:25404403, ECO:0000269|PubMed:28604766};
DE AltName: Full=Deubiquitinating enzyme 4;
DE AltName: Full=Ubiquitin thioesterase 4;
DE AltName: Full=Ubiquitin-specific-processing protease 4;
DE AltName: Full=Ubiquitous nuclear protein homolog;
GN Name=USP4; Synonyms=UNP, UNPH;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND TISSUE SPECIFICITY.
RC TISSUE=Brain cortex;
RX PubMed=7784062;
RA Gray D.A., Inazawa J., Gupta K., Wong A., Ueda R., Takahashi T.;
RT "Elevated expression of Unph, a proto-oncogene at 3p21.3, in human lung
RT tumors.";
RL Oncogene 10:2179-2183(1995).
RN [2]
RP SEQUENCE REVISION.
RA Gray D.A.;
RL Submitted (OCT-1997) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), AND ALTERNATIVE SPLICING.
RC TISSUE=B-cell, and T-cell;
RX PubMed=9464533; DOI=10.1038/sj.onc.1201537;
RA Frederick A., Rolfe M., Chiu M.I.;
RT "The human UNP locus at 3p21.31 encodes two tissue-selective, cytoplasmic
RT isoforms with deubiquitinating activity that have reduced expression in
RT small cell lung carcinoma cell lines.";
RL Oncogene 16:153-165(1998).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Placenta;
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16641997; DOI=10.1038/nature04728;
RA Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R., Buhay C.J.,
RA Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R., Gunaratne P.,
RA Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V., Hume J., Jackson A.,
RA Khan Z.M., Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L.,
RA Milosavljevic A., Miner G.R., Morgan M.B., Nazareth L.V., Scott G.,
RA Sodergren E., Song X.-Z., Steffen D., Wei S., Wheeler D.A., Wright M.W.,
RA Worley K.C., Yuan Y., Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M.,
RA Brown M.J., Chen G., Chen Z., Clendenning J., Clerc-Blankenburg K.P.,
RA Chen R., Chen Z., Davis C., Delgado O., Dinh H.H., Dong W., Draper H.,
RA Ernst S., Fu G., Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J.,
RA Hao B., Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W.,
RA Jackson L.R., Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B.,
RA Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O.,
RA Palmeiri A., Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B.,
RA Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H.,
RA Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J.,
RA Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J., Zhang X.,
RA Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H., Reinhardt R.,
RA Naylor S.L., Yang H., Olson M., Weinstock G., Gibbs R.A.;
RT "The DNA sequence, annotation and analysis of human chromosome 3.";
RL Nature 440:1194-1198(2006).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 3).
RC TISSUE=Leukocyte;
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 INTERACTION WITH RB1, AND MUTAGENESIS OF GLU-463 AND 459-LEU--GLU-463.
RX PubMed=11571652; DOI=10.1038/sj.onc.1204824;
RA DeSalle L.M., Latres E., Lin D., Graner E., Montagnoli A., Baker R.T.,
RA Pagano M., Loda M.;
RT "The de-ubiquitinating enzyme Unp interacts with the retinoblastoma
RT protein.";
RL Oncogene 20:5538-5542(2001).
RN [8]
RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, AND MUTAGENESIS OF
RP CYS-311.
RX PubMed=16316627; DOI=10.1016/j.bbrc.2005.11.076;
RA Wada K., Tanji K., Kamitani T.;
RT "Oncogenic protein UnpEL/Usp4 deubiquitinates Ro52 by its isopeptidase
RT activity.";
RL Biochem. Biophys. Res. Commun. 339:731-736(2006).
RN [9]
RP FUNCTION, CATALYTIC ACTIVITY, AUTODEUBIQUITINATION, UBIQUITINATION BY
RP TRIM21, AND MUTAGENESIS OF CYS-311.
RX PubMed=16472766; DOI=10.1016/j.bbrc.2006.01.144;
RA Wada K., Kamitani T.;
RT "UnpEL/Usp4 is ubiquitinated by Ro52 and deubiquitinated by itself.";
RL Biochem. Biophys. Res. Commun. 342:253-258(2006).
RN [10]
RP FUNCTION, CATALYTIC ACTIVITY, INTERACTION WITH ADORA2A, AND TISSUE
RP SPECIFICITY.
RX PubMed=16339847; DOI=10.1124/mol.105.015818;
RA Milojevic T., Reiterer V., Stefan E., Korkhov V.M., Dorostkar M.M.,
RA Ducza E., Ogris E., Boehm S., Freissmuth M., Nanoff C.;
RT "The ubiquitin-specific protease Usp4 regulates the cell surface level of
RT the A2A receptor.";
RL Mol. Pharmacol. 69:1083-1094(2006).
RN [11]
RP FUNCTION, CATALYTIC ACTIVITY, INTERACTION WITH SART3, AND SUBCELLULAR
RP LOCATION.
RX PubMed=20595234; DOI=10.1101/gad.1925010;
RA Song E.J., Werner S.L., Neubauer J., Stegmeier F., Aspden J., Rio D.,
RA Harper J.W., Elledge S.J., Kirschner M.W., Rape M.;
RT "The Prp19 complex and the Usp4Sart3 deubiquitinating enzyme control
RT reversible ubiquitination at the spliceosome.";
RL Genes Dev. 24:1434-1447(2010).
RN [12]
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 [13]
RP RETRACTED PAPER.
RX PubMed=21415856; DOI=10.1038/embor.2011.33;
RA Luna-Vargas M.P., Faesen A.C., van Dijk W.J., Rape M., Fish A., Sixma T.K.;
RT "Ubiquitin-specific protease 4 is inhibited by its ubiquitin-like domain.";
RL EMBO Rep. 12:365-372(2011).
RN [14]
RP RETRACTION NOTICE OF PUBMED:21415856.
RX PubMed=24398133; DOI=10.1002/embr.201470010;
RA Luna-Vargas M.P., Faesen A.C., van Dijk W.J., Rape M., Fish A., Sixma T.K.;
RT "Retraction: 'Ubiquitin-specific protease 4 is inhibited by its ubiquitin-
RT like domain' by MP Luna-Vargas, AC Faesen, WJ van Dijk, M Rape, A Fish, TK
RT Sixma.";
RL EMBO Rep. 15:121-121(2014).
RN [15]
RP FUNCTION, DEUBIQUITINATION OF PDPK1, AND CATALYTIC ACTIVITY.
RX PubMed=22347420; DOI=10.1371/journal.pone.0031003;
RA Uras I.Z., List T., Nijman S.M.;
RT "Ubiquitin-specific protease 4 inhibits mono-ubiquitination of the master
RT growth factor signaling kinase PDK1.";
RL PLoS ONE 7:E31003-E31003(2012).
RN [16]
RP X-RAY CRYSTALLOGRAPHY (2.40 ANGSTROMS) OF 296-490 AND 765-932 IN COMPLEX
RP WITH ZINC, FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES,
RP DOMAIN, AND MUTAGENESIS OF MET-24; ARG-40; PHE-51; ILE-88; ASP-89; GLU-90;
RP LEU-91; ASP-92; GLU-134; TYR-136; 384-PRO--GLN-385 AND PHE-386.
RX PubMed=25404403; DOI=10.1038/ncomms6399;
RA Clerici M., Luna-Vargas M.P., Faesen A.C., Sixma T.K.;
RT "The DUSP-Ubl domain of USP4 enhances its catalytic efficiency by promoting
RT ubiquitin exchange.";
RL Nat. Commun. 5:5399-5399(2014).
RN [17]
RP FUNCTION, CATALYTIC ACTIVITY, DEUBIQUITINATION OF HAS2, AND MUTAGENESIS OF
RP CYS-311.
RX PubMed=28604766; DOI=10.1038/oncsis.2017.45;
RA Mehic M., de Sa V.K., Hebestreit S., Heldin C.H., Heldin P.;
RT "The deubiquitinating enzymes USP4 and USP17 target hyaluronan synthase 2
RT and differentially affect its function.";
RL Oncogenesis 6:e348-e348(2017).
CC -!- FUNCTION: Deubiquitinating enzyme that removes conjugated ubiquitin
CC from target proteins (PubMed:16316627, PubMed:16472766,
CC PubMed:16339847, PubMed:20595234, PubMed:22347420, PubMed:25404403,
CC PubMed:28604766). Deubiquitinates PDPK1 (PubMed:22347420).
CC Deubiquitinates TRIM21 (PubMed:16316627). Deubiquitinates receptor
CC ADORA2A which increases the amount of functional receptor at the cell
CC surface (PubMed:16339847). Deubiquitinates HAS2 (PubMed:28604766). May
CC regulate mRNA splicing through deubiquitination of the U4 spliceosomal
CC protein PRPF3 (PubMed:20595234). This may prevent its recognition by
CC the U5 component PRPF8 thereby destabilizing interactions within the
CC U4/U6.U5 snRNP (PubMed:20595234). May also play a role in the
CC regulation of quality control in the ER (PubMed:16339847).
CC {ECO:0000269|PubMed:16316627, ECO:0000269|PubMed:16339847,
CC ECO:0000269|PubMed:16472766, ECO:0000269|PubMed:20595234,
CC ECO:0000269|PubMed:22347420, ECO:0000269|PubMed:25404403,
CC ECO:0000269|PubMed:28604766}.
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:16316627,
CC ECO:0000269|PubMed:16339847, ECO:0000269|PubMed:16472766,
CC ECO:0000269|PubMed:20595234, ECO:0000269|PubMed:22347420,
CC ECO:0000269|PubMed:25404403, ECO:0000269|PubMed:28604766};
CC -!- ACTIVITY REGULATION: The completion of the deubiquitinase reaction is
CC mediated by the DUSP and ubiquitin-like 1 domains which promotes the
CC release of ubiquitin from the catalytic site enabling subsequent
CC reactions to occur. {ECO:0000269|PubMed:25404403}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=0.15 uM for ubiquitin-rhodamine {ECO:0000269|PubMed:25404403};
CC -!- SUBUNIT: Interacts with RB1 (both dephosphorylated and
CC hypophosphorylated forms) (PubMed:11571652). Interacts with RBL1 and
CC RBL2 (By similarity). Interacts with ADORA2A (via cytoplasmic C-
CC terminus); the interaction is direct (PubMed:16339847). Interacts with
CC SART3; recruits USP4 to its substrate PRPF3 (PubMed:20595234).
CC {ECO:0000250|UniProtKB:P35123, ECO:0000269|PubMed:11571652,
CC ECO:0000269|PubMed:16339847, ECO:0000269|PubMed:20595234}.
CC -!- INTERACTION:
CC Q13107; P29274: ADORA2A; NbExp=4; IntAct=EBI-723290, EBI-2902702;
CC Q13107; Q7Z6Z7: HUWE1; NbExp=4; IntAct=EBI-723290, EBI-625934;
CC Q13107; Q13546: RIPK1; NbExp=4; IntAct=EBI-723290, EBI-358507;
CC Q13107; Q13107: USP4; NbExp=3; IntAct=EBI-723290, EBI-723290;
CC Q13107-1; P19474: TRIM21; NbExp=3; IntAct=EBI-723305, EBI-81290;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:16316627,
CC ECO:0000269|PubMed:20595234}. Nucleus {ECO:0000269|PubMed:16316627,
CC ECO:0000269|PubMed:20595234}. Note=Shuttles between the nucleus and
CC cytoplasm. Exported to the cytoplasm in a CRM1-dependent manner and
CC recycled back to the nucleus via the importin alpha/beta heterodimeric
CC import receptor. The relative amounts found in the nucleus and
CC cytoplasm vary according to the cell type.
CC {ECO:0000269|PubMed:16316627, ECO:0000269|PubMed:20595234}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1; Synonyms=UnpEL;
CC IsoId=Q13107-1; Sequence=Displayed;
CC Name=2; Synonyms=UnpES;
CC IsoId=Q13107-2; Sequence=VSP_005258;
CC Name=3;
CC IsoId=Q13107-3; Sequence=VSP_044814, VSP_044815;
CC -!- TISSUE SPECIFICITY: Overexpressed in small cell tumors and
CC adenocarcinomas of the lung compared to wild-type lung (at protein
CC level). Expressed in the hippocampal neurons.
CC {ECO:0000269|PubMed:16339847, ECO:0000269|PubMed:7784062}.
CC -!- DOMAIN: The DUSP and ubiquitin-like 1 domains promote ubiquitin release
CC and thus enhance USB4 catalytic activity. However, these domains do not
CC bind ubiquitin. {ECO:0000269|PubMed:25404403}.
CC -!- PTM: Monoubiquitinated by TRIM21. Ubiquitination does not lead to its
CC proteasomal degradation. Autodeubiquitinated.
CC {ECO:0000269|PubMed:16472766, ECO:0000269|PubMed:22347420}.
CC -!- SIMILARITY: Belongs to the peptidase C19 family. USP4 subfamily.
CC {ECO:0000305}.
CC -!- CAUTION: The ubiquitin-like domain 2 was thought to interact with the
CC catalytic domain competing with the ubiquitin substrate and thus
CC partially inhibiting USP4 activity (PubMed:21415856). As the results
CC could not be reproduced this work was later retracted
CC (PubMed:24398133). The cristal structure in the paper was correct and
CC was republished later (PubMed:25404403). {ECO:0000269|PubMed:21415856,
CC ECO:0000269|PubMed:24398133, ECO:0000269|PubMed:25404403}.
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DR EMBL; U20657; AAB72237.1; -; mRNA.
DR EMBL; AF017305; AAC27355.1; -; mRNA.
DR EMBL; AF017306; AAC27356.1; -; mRNA.
DR EMBL; AK291795; BAF84484.1; -; mRNA.
DR EMBL; AC121247; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC068017; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; BC125130; AAI25131.1; -; mRNA.
DR CCDS; CCDS2793.1; -. [Q13107-1]
DR CCDS; CCDS2794.1; -. [Q13107-2]
DR CCDS; CCDS58832.1; -. [Q13107-3]
DR PIR; T09478; T09478.
DR RefSeq; NP_001238806.1; NM_001251877.1. [Q13107-3]
DR RefSeq; NP_003354.2; NM_003363.3. [Q13107-1]
DR RefSeq; NP_955475.1; NM_199443.2. [Q13107-2]
DR PDB; 2Y6E; X-ray; 2.40 A; A/B/C/D/E/F=296-490, A/B/C/D/E/F=765-932.
DR PDB; 5CTR; X-ray; 3.01 A; C/D=1-230.
DR PDBsum; 2Y6E; -.
DR PDBsum; 5CTR; -.
DR AlphaFoldDB; Q13107; -.
DR SMR; Q13107; -.
DR BioGRID; 113221; 161.
DR IntAct; Q13107; 56.
DR MINT; Q13107; -.
DR STRING; 9606.ENSP00000265560; -.
DR BindingDB; Q13107; -.
DR ChEMBL; CHEMBL2406900; -.
DR MEROPS; C19.010; -.
DR GlyGen; Q13107; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; Q13107; -.
DR PhosphoSitePlus; Q13107; -.
DR BioMuta; USP4; -.
DR DMDM; 116242839; -.
DR EPD; Q13107; -.
DR jPOST; Q13107; -.
DR MassIVE; Q13107; -.
DR MaxQB; Q13107; -.
DR PaxDb; Q13107; -.
DR PeptideAtlas; Q13107; -.
DR PRIDE; Q13107; -.
DR ProteomicsDB; 59158; -. [Q13107-1]
DR ProteomicsDB; 59159; -. [Q13107-2]
DR ProteomicsDB; 7631; -.
DR Antibodypedia; 13556; 381 antibodies from 32 providers.
DR DNASU; 7375; -.
DR Ensembl; ENST00000265560.9; ENSP00000265560.4; ENSG00000114316.13. [Q13107-1]
DR Ensembl; ENST00000351842.8; ENSP00000341028.4; ENSG00000114316.13. [Q13107-2]
DR Ensembl; ENST00000416417.5; ENSP00000400623.1; ENSG00000114316.13. [Q13107-3]
DR GeneID; 7375; -.
DR KEGG; hsa:7375; -.
DR MANE-Select; ENST00000265560.9; ENSP00000265560.4; NM_003363.4; NP_003354.2.
DR UCSC; uc003cwq.3; human. [Q13107-1]
DR CTD; 7375; -.
DR DisGeNET; 7375; -.
DR GeneCards; USP4; -.
DR HGNC; HGNC:12627; USP4.
DR HPA; ENSG00000114316; Low tissue specificity.
DR MIM; 603486; gene.
DR neXtProt; NX_Q13107; -.
DR OpenTargets; ENSG00000114316; -.
DR PharmGKB; PA37252; -.
DR VEuPathDB; HostDB:ENSG00000114316; -.
DR eggNOG; KOG1870; Eukaryota.
DR GeneTree; ENSGT00940000156645; -.
DR HOGENOM; CLU_001060_7_1_1; -.
DR InParanoid; Q13107; -.
DR OMA; SGTCNEA; -.
DR PhylomeDB; Q13107; -.
DR TreeFam; TF106276; -.
DR PathwayCommons; Q13107; -.
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-5689880; Ub-specific processing proteases.
DR SignaLink; Q13107; -.
DR BioGRID-ORCS; 7375; 12 hits in 1090 CRISPR screens.
DR ChiTaRS; USP4; human.
DR EvolutionaryTrace; Q13107; -.
DR GeneWiki; USP4; -.
DR GenomeRNAi; 7375; -.
DR Pharos; Q13107; Tchem.
DR PRO; PR:Q13107; -.
DR Proteomes; UP000005640; Chromosome 3.
DR RNAct; Q13107; protein.
DR Bgee; ENSG00000114316; Expressed in pancreatic ductal cell and 205 other tissues.
DR ExpressionAtlas; Q13107; baseline and differential.
DR Genevisible; Q13107; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0005764; C:lysosome; TAS:ProtInc.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR GO; GO:0031685; F:adenosine receptor binding; IPI:UniProtKB.
DR GO; GO:0004843; F:cysteine-type deubiquitinase activity; IDA:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0031397; P:negative regulation of protein ubiquitination; IMP:UniProtKB.
DR GO; GO:0016579; P:protein deubiquitination; IDA:UniProtKB.
DR GO; GO:0034394; P:protein localization to cell surface; IDA:UniProtKB.
DR GO; GO:0031647; P:regulation of protein stability; IDA:UniProtKB.
DR GO; GO:0000244; P:spliceosomal tri-snRNP complex assembly; IMP:UniProtKB.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IEA:InterPro.
DR Gene3D; 3.30.2230.10; -; 1.
DR InterPro; IPR035927; DUSP-like_sf.
DR InterPro; IPR038765; Papain-like_cys_pep_sf.
DR InterPro; IPR006615; Pept_C19_DUSP.
DR InterPro; IPR001394; Peptidase_C19_UCH.
DR InterPro; IPR028135; Ub_USP-typ.
DR InterPro; IPR018200; USP_CS.
DR InterPro; IPR028889; USP_dom.
DR Pfam; PF06337; DUSP; 1.
DR Pfam; PF14836; Ubiquitin_3; 1.
DR Pfam; PF00443; UCH; 1.
DR SMART; SM00695; DUSP; 1.
DR SUPFAM; SSF143791; SSF143791; 1.
DR SUPFAM; SSF54001; SSF54001; 1.
DR PROSITE; PS51283; DUSP; 1.
DR PROSITE; PS00972; USP_1; 1.
DR PROSITE; PS00973; USP_2; 1.
DR PROSITE; PS50235; USP_3; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cytoplasm; Hydrolase; Metal-binding;
KW Nucleus; Phosphoprotein; Protease; Proto-oncogene; Reference proteome;
KW Repeat; Thiol protease; Ubl conjugation; Ubl conjugation pathway; Zinc.
FT CHAIN 1..963
FT /note="Ubiquitin carboxyl-terminal hydrolase 4"
FT /id="PRO_0000080621"
FT DOMAIN 11..122
FT /note="DUSP"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00613"
FT DOMAIN 142..226
FT /note="Ubiquitin-like 1"
FT /evidence="ECO:0000255"
FT DOMAIN 302..923
FT /note="USP"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01035"
FT DOMAIN 483..571
FT /note="Ubiquitin-like 2"
FT /evidence="ECO:0000255"
FT REGION 1..22
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 27..216
FT /note="Necessary for interaction with SART3"
FT /evidence="ECO:0000269|PubMed:20595234"
FT REGION 219..253
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 229..295
FT /note="Required for USP4 activation by providing
FT conformational flexibility between the DUSP and catalytic
FT domains"
FT /evidence="ECO:0000269|PubMed:25404403"
FT REGION 384..386
FT /note="Regulates ubiquitin dissociation"
FT /evidence="ECO:0000269|PubMed:25404403"
FT REGION 405..407
FT /note="Necessary for interaction with RBL2"
FT /evidence="ECO:0000250|UniProtKB:P35123"
FT REGION 459..463
FT /note="Necessary for interaction with RB1 and RBL2"
FT /evidence="ECO:0000250|UniProtKB:P35123,
FT ECO:0000269|PubMed:11571652"
FT REGION 485..775
FT /note="Interacts with DUSP and ubiquitin-like 1 domains and
FT is required for USP4 activation"
FT /evidence="ECO:0000269|PubMed:25404403"
FT REGION 637..699
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 928..963
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 133..141
FT /note="Nuclear export signal"
FT /evidence="ECO:0000250|UniProtKB:P35123"
FT MOTIF 767..772
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000250|UniProtKB:P35123"
FT COMPBIAS 1..16
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 221..253
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 930..963
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 311
FT /note="Nucleophile"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01035"
FT ACT_SITE 881
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01035"
FT BINDING 461
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000269|PubMed:25404403,
FT ECO:0007744|PDB:2Y6E"
FT BINDING 464
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000269|PubMed:25404403,
FT ECO:0007744|PDB:2Y6E"
FT BINDING 799
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000269|PubMed:25404403,
FT ECO:0007744|PDB:2Y6E"
FT BINDING 802
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000269|PubMed:25404403,
FT ECO:0007744|PDB:2Y6E"
FT MOD_RES 655
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:B2GUZ1"
FT MOD_RES 675
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P35123"
FT MOD_RES 680
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P35123"
FT VAR_SEQ 232..279
FT /note="KSSTAPSRNFTTSPKSSASPYSSVSASLIANGDSTSTCGMHSSGVSRG ->
FT N (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:9464533"
FT /id="VSP_005258"
FT VAR_SEQ 233..313
FT /note="SSTAPSRNFTTSPKSSASPYSSVSASLIANGDSTSTCGMHSSGVSRGGSGFS
FT ASYNCQEPPSSHIQPGLCGLGNLGNTCFM -> VSFFLPRLECNGAILAHCNFCLPGSS
FT NSPASASRVAPSHLANFFFFEMESHSVTKLECGGAVSAYSRVQVMLLPQPPEWLG (in
FT isoform 3)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_044814"
FT VAR_SEQ 314..963
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_044815"
FT VARIANT 620
FT /note="Y -> C (in dbSNP:rs9311440)"
FT /id="VAR_028180"
FT MUTAGEN 24
FT /note="M->D: Moderate reduction in thiol-dependent
FT deubiquitinase activity."
FT /evidence="ECO:0000269|PubMed:25404403"
FT MUTAGEN 40
FT /note="R->E: Moderate reduction in thiol-dependent
FT deubiquitinase activity."
FT /evidence="ECO:0000269|PubMed:25404403"
FT MUTAGEN 51
FT /note="F->D: Moderate reduction in thiol-dependent
FT deubiquitinase activity."
FT /evidence="ECO:0000269|PubMed:25404403"
FT MUTAGEN 88
FT /note="I->P: Severe reduction in thiol-dependent
FT deubiquitinase activity."
FT /evidence="ECO:0000269|PubMed:25404403"
FT MUTAGEN 88
FT /note="I->R: Moderate reduction in thiol-dependent
FT deubiquitinase activity."
FT /evidence="ECO:0000269|PubMed:25404403"
FT MUTAGEN 89
FT /note="D->G: Severe reduction in thiol-dependent
FT deubiquitinase activity."
FT /evidence="ECO:0000269|PubMed:25404403"
FT MUTAGEN 90
FT /note="E->A: Moderate reduction in thiol-dependent
FT deubiquitinase activity."
FT /evidence="ECO:0000269|PubMed:25404403"
FT MUTAGEN 91
FT /note="L->E: Moderate reduction in thiol-dependent
FT deubiquitinase activity."
FT /evidence="ECO:0000269|PubMed:25404403"
FT MUTAGEN 92
FT /note="D->R: Severe reduction in thiol-dependent
FT deubiquitinase activity."
FT /evidence="ECO:0000269|PubMed:25404403"
FT MUTAGEN 134
FT /note="E->A: Severe reduction in thiol-dependent
FT deubiquitinase activity."
FT /evidence="ECO:0000269|PubMed:25404403"
FT MUTAGEN 136
FT /note="Y->A: Severe reduction in thiol-dependent
FT deubiquitinase activity."
FT /evidence="ECO:0000269|PubMed:25404403"
FT MUTAGEN 311
FT /note="C->A: Loss of thiol-dependent deubiquitinase
FT activity. Its ubiquitination by TRIM21 is enhanced. Does
FT affect interaction with HAS2. Does not deubiquitinate
FT HAS2."
FT /evidence="ECO:0000269|PubMed:16316627,
FT ECO:0000269|PubMed:16472766, ECO:0000269|PubMed:28604766"
FT MUTAGEN 384..385
FT /note="PQ->AV: Severe reduction in thiol-dependent
FT deubiquitinase activity."
FT /evidence="ECO:0000269|PubMed:25404403"
FT MUTAGEN 386
FT /note="F->G: Lowers affinity for ubiquitin characterized by
FT a 10-fold increase in ubiquitin release and a slight
FT reduction in ubiquitin binding."
FT /evidence="ECO:0000269|PubMed:25404403"
FT MUTAGEN 459..463
FT /note="LVCPE->AVRPH: Reduces the interaction with RB1."
FT /evidence="ECO:0000269|PubMed:11571652"
FT MUTAGEN 463
FT /note="E->Q: Reduces the interaction with RB1."
FT /evidence="ECO:0000269|PubMed:11571652"
FT CONFLICT 373
FT /note="R -> S (in Ref. 1; AAB72237)"
FT /evidence="ECO:0000305"
FT CONFLICT 744
FT /note="S -> R (in Ref. 1; AAB72237)"
FT /evidence="ECO:0000305"
FT HELIX 13..20
FT /evidence="ECO:0007829|PDB:5CTR"
FT HELIX 21..23
FT /evidence="ECO:0007829|PDB:5CTR"
FT STRAND 32..38
FT /evidence="ECO:0007829|PDB:5CTR"
FT HELIX 39..48
FT /evidence="ECO:0007829|PDB:5CTR"
FT HELIX 62..64
FT /evidence="ECO:0007829|PDB:5CTR"
FT TURN 72..74
FT /evidence="ECO:0007829|PDB:5CTR"
FT STRAND 75..77
FT /evidence="ECO:0007829|PDB:5CTR"
FT TURN 78..81
FT /evidence="ECO:0007829|PDB:5CTR"
FT TURN 89..92
FT /evidence="ECO:0007829|PDB:5CTR"
FT STRAND 93..97
FT /evidence="ECO:0007829|PDB:5CTR"
FT HELIX 98..108
FT /evidence="ECO:0007829|PDB:5CTR"
FT STRAND 118..124
FT /evidence="ECO:0007829|PDB:5CTR"
FT STRAND 126..128
FT /evidence="ECO:0007829|PDB:5CTR"
FT STRAND 130..133
FT /evidence="ECO:0007829|PDB:5CTR"
FT STRAND 140..143
FT /evidence="ECO:0007829|PDB:5CTR"
FT STRAND 151..154
FT /evidence="ECO:0007829|PDB:5CTR"
FT STRAND 158..161
FT /evidence="ECO:0007829|PDB:5CTR"
FT HELIX 162..172
FT /evidence="ECO:0007829|PDB:5CTR"
FT STRAND 177..179
FT /evidence="ECO:0007829|PDB:5CTR"
FT STRAND 183..185
FT /evidence="ECO:0007829|PDB:5CTR"
FT STRAND 187..191
FT /evidence="ECO:0007829|PDB:5CTR"
FT STRAND 198..202
FT /evidence="ECO:0007829|PDB:5CTR"
FT TURN 203..206
FT /evidence="ECO:0007829|PDB:5CTR"
FT HELIX 311..321
FT /evidence="ECO:0007829|PDB:2Y6E"
FT HELIX 324..331
FT /evidence="ECO:0007829|PDB:2Y6E"
FT HELIX 335..338
FT /evidence="ECO:0007829|PDB:2Y6E"
FT HELIX 350..362
FT /evidence="ECO:0007829|PDB:2Y6E"
FT STRAND 364..366
FT /evidence="ECO:0007829|PDB:2Y6E"
FT STRAND 368..370
FT /evidence="ECO:0007829|PDB:2Y6E"
FT HELIX 373..382
FT /evidence="ECO:0007829|PDB:2Y6E"
FT HELIX 384..386
FT /evidence="ECO:0007829|PDB:2Y6E"
FT STRAND 388..390
FT /evidence="ECO:0007829|PDB:2Y6E"
FT HELIX 394..408
FT /evidence="ECO:0007829|PDB:2Y6E"
FT HELIX 428..442
FT /evidence="ECO:0007829|PDB:2Y6E"
FT HELIX 446..451
FT /evidence="ECO:0007829|PDB:2Y6E"
FT STRAND 453..460
FT /evidence="ECO:0007829|PDB:2Y6E"
FT TURN 462..464
FT /evidence="ECO:0007829|PDB:2Y6E"
FT STRAND 467..480
FT /evidence="ECO:0007829|PDB:2Y6E"
FT HELIX 778..785
FT /evidence="ECO:0007829|PDB:2Y6E"
FT STRAND 797..799
FT /evidence="ECO:0007829|PDB:2Y6E"
FT TURN 800..803
FT /evidence="ECO:0007829|PDB:2Y6E"
FT STRAND 804..806
FT /evidence="ECO:0007829|PDB:2Y6E"
FT STRAND 809..816
FT /evidence="ECO:0007829|PDB:2Y6E"
FT STRAND 819..826
FT /evidence="ECO:0007829|PDB:2Y6E"
FT STRAND 828..830
FT /evidence="ECO:0007829|PDB:2Y6E"
FT STRAND 835..837
FT /evidence="ECO:0007829|PDB:2Y6E"
FT HELIX 852..854
FT /evidence="ECO:0007829|PDB:2Y6E"
FT STRAND 858..860
FT /evidence="ECO:0007829|PDB:2Y6E"
FT STRAND 864..874
FT /evidence="ECO:0007829|PDB:2Y6E"
FT STRAND 876..879
FT /evidence="ECO:0007829|PDB:2Y6E"
FT STRAND 881..887
FT /evidence="ECO:0007829|PDB:2Y6E"
FT TURN 889..891
FT /evidence="ECO:0007829|PDB:2Y6E"
FT STRAND 894..898
FT /evidence="ECO:0007829|PDB:2Y6E"
FT STRAND 901..904
FT /evidence="ECO:0007829|PDB:2Y6E"
FT HELIX 907..909
FT /evidence="ECO:0007829|PDB:2Y6E"
FT STRAND 915..922
FT /evidence="ECO:0007829|PDB:2Y6E"
FT HELIX 926..928
FT /evidence="ECO:0007829|PDB:2Y6E"
SQ SEQUENCE 963 AA; 108565 MW; 63055C9ADFE36713 CRC64;
MAEGGGCRER PDAETQKSEL GPLMRTTLQR GAQWYLIDSR WFKQWKKYVG FDSWDMYNVG
EHNLFPGPID NSGLFSDPES QTLKEHLIDE LDYVLVPTEA WNKLLNWYGC VEGQQPIVRK
VVEHGLFVKH CKVEVYLLEL KLCENSDPTN VLSCHFSKAD TIATIEKEMR KLFNIPAERE
TRLWNKYMSN TYEQLSKLDN TVQDAGLYQG QVLVIEPQNE DGTWPRQTLQ SKSSTAPSRN
FTTSPKSSAS PYSSVSASLI ANGDSTSTCG MHSSGVSRGG SGFSASYNCQ EPPSSHIQPG
LCGLGNLGNT CFMNSALQCL SNTAPLTDYF LKDEYEAEIN RDNPLGMKGE IAEAYAELIK
QMWSGRDAHV APRMFKTQVG RFAPQFSGYQ QQDSQELLAF LLDGLHEDLN RVKKKPYLEL
KDANGRPDAV VAKEAWENHR LRNDSVIVDT FHGLFKSTLV CPECAKVSVT FDPFCYLTLP
LPLKKDRVME VFLVPADPHC RPTQYRVTVP LMGAVSDLCE ALSRLSGIAA ENMVVADVYN
HRFHKIFQMD EGLNHIMPRD DIFVYEVCST SVDGSECVTL PVYFRERKSR PSSTSSASAL
YGQPLLLSVP KHKLTLESLY QAVCDRISRY VKQPLPDEFG SSPLEPGACN GSRNSCEGED
EEEMEHQEEG KEQLSETEGS GEDEPGNDPS ETTQKKIKGQ PCPKRLFTFS LVNSYGTADI
NSLAADGKLL KLNSRSTLAM DWDSETRRLY YDEQESEAYE KHVSMLQPQK KKKTTVALRD
CIELFTTMET LGEHDPWYCP NCKKHQQATK KFDLWSLPKI LVVHLKRFSY NRYWRDKLDT
VVEFPIRGLN MSEFVCNLSA RPYVYDLIAV SNHYGAMGVG HYTAYAKNKL NGKWYYFDDS
NVSLASEDQI VTKAAYVLFY QRRDDEFYKT PSLSSSGSSD GGTRPSSSQQ GFGDDEACSM
DTN
