ID   UBP4_RAT                Reviewed;         961 AA.
AC   B2GUZ1;
DT   10-AUG-2010, integrated into UniProtKB/Swiss-Prot.
DT   10-JUN-2008, sequence version 1.
DT   27-MAR-2024, entry version 101.
DE   RecName: Full=Ubiquitin carboxyl-terminal hydrolase 4;
DE            EC=3.4.19.12 {ECO:0000250|UniProtKB:Q13107};
DE   AltName: Full=Deubiquitinating enzyme 4;
DE   AltName: Full=Ubiquitin thioesterase 4;
DE   AltName: Full=Ubiquitin-specific-processing protease 4;
GN   Name=Usp4;
OS   Rattus norvegicus (Rat).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC   Murinae; Rattus.
OX   NCBI_TaxID=10116;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC   STRAIN=Brown Norway;
RA   Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.;
RL   Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Lung;
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   [3]
RP   TISSUE 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   [4]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-655 AND SER-674, AND
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=22673903; DOI=10.1038/ncomms1871;
RA   Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA   Olsen J.V.;
RT   "Quantitative maps of protein phosphorylation sites across 14 different rat
RT   organs and tissues.";
RL   Nat. Commun. 3:876-876(2012).
CC   -!- FUNCTION: Deubiquitinating enzyme that removes conjugated ubiquitin
CC       from target proteins. Deubiquitinates PDPK1. Deubiquitinates TRIM21.
CC       Deubiquitinates receptor ADORA2A which increases the amount of
CC       functional receptor at the cell surface. Deubiquitinates HAS2.
CC       Deubiquitinates RHEB in response to EGF signaling, promoting mTORC1
CC       signaling. May regulate mRNA splicing through deubiquitination of the
CC       U4 spliceosomal protein PRPF3. This may prevent its recognition by the
CC       U5 component PRPF8 thereby destabilizing interactions within the
CC       U4/U6.U5 snRNP. May also play a role in the regulation of quality
CC       control in the ER. {ECO:0000250|UniProtKB:Q13107}.
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:0000250|UniProtKB:Q13107};
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:0000250|UniProtKB:Q13107}.
CC   -!- SUBUNIT: Interacts with RB1 (both dephosphorylated and
CC       hypophosphorylated forms) (By similarity). Interacts with RBL1 and RBL2
CC       (By similarity). Interacts with ADORA2A (via cytoplasmic C-terminus);
CC       the interaction is direct. Interacts with SART3; recruits USP4 to its
CC       substrate PRPF3 (By similarity). {ECO:0000250|UniProtKB:P35123,
CC       ECO:0000250|UniProtKB:Q13107}.
CC   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:P35123,
CC       ECO:0000250|UniProtKB:Q13107}. Nucleus {ECO:0000250|UniProtKB:P35123,
CC       ECO:0000250|UniProtKB:Q13107}. 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:0000250|UniProtKB:P35123, ECO:0000250|UniProtKB:Q13107}.
CC   -!- TISSUE SPECIFICITY: Expressed in hippocampus and striatum (at protein
CC       level). {ECO:0000269|PubMed:16339847}.
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:0000250|UniProtKB:Q13107}.
CC   -!- PTM: Phosphorylated at Ser-445 by PKB/AKT1 in response to EGF stimulus,
CC       promoting its ability deubiquitinate RHEB.
CC       {ECO:0000250|UniProtKB:Q13107}.
CC   -!- PTM: Monoubiquitinated by TRIM21. Ubiquitination does not lead to its
CC       proteasomal degradation. Autodeubiquitinated.
CC       {ECO:0000250|UniProtKB:Q13107}.
CC   -!- SIMILARITY: Belongs to the peptidase C19 family. USP4 subfamily.
CC       {ECO:0000305}.
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DR   EMBL; BC166460; AAI66460.1; -; mRNA.
DR   EMBL; CH473954; EDL77177.1; -; Genomic_DNA.
DR   RefSeq; NP_001128484.1; NM_001135012.1.
DR   AlphaFoldDB; B2GUZ1; -.
DR   SMR; B2GUZ1; -.
DR   BioGRID; 253348; 1.
DR   IntAct; B2GUZ1; 2.
DR   STRING; 10116.ENSRNOP00000071463; -.
DR   iPTMnet; B2GUZ1; -.
DR   PhosphoSitePlus; B2GUZ1; -.
DR   jPOST; B2GUZ1; -.
DR   PaxDb; 10116-ENSRNOP00000066449; -.
DR   PeptideAtlas; B2GUZ1; -.
DR   Ensembl; ENSRNOT00000083046.2; ENSRNOP00000071463.1; ENSRNOG00000054863.2.
DR   Ensembl; ENSRNOT00055023041; ENSRNOP00055018684; ENSRNOG00055013447.
DR   Ensembl; ENSRNOT00060042387; ENSRNOP00060035127; ENSRNOG00060024441.
DR   Ensembl; ENSRNOT00065010237; ENSRNOP00065007471; ENSRNOG00065006618.
DR   GeneID; 290864; -.
DR   KEGG; rno:290864; -.
DR   AGR; RGD:1587387; -.
DR   CTD; 7375; -.
DR   RGD; 1587387; Usp4.
DR   eggNOG; KOG1870; Eukaryota.
DR   GeneTree; ENSGT00940000156645; -.
DR   InParanoid; B2GUZ1; -.
DR   OMA; ALKWHHD; -.
DR   OrthoDB; 5474185at2759; -.
DR   PhylomeDB; B2GUZ1; -.
DR   Reactome; R-RNO-5357786; TNFR1-induced proapoptotic signaling.
DR   Reactome; R-RNO-5357905; Regulation of TNFR1 signaling.
DR   Reactome; R-RNO-5357956; TNFR1-induced NF-kappa-B signaling pathway.
DR   Reactome; R-RNO-5689880; Ub-specific processing proteases.
DR   PRO; PR:B2GUZ1; -.
DR   Proteomes; UP000002494; Chromosome 8.
DR   Proteomes; UP000234681; Chromosome 8.
DR   Bgee; ENSRNOG00000054863; Expressed in skeletal muscle tissue and 19 other cell types or tissues.
DR   ExpressionAtlas; B2GUZ1; baseline and differential.
DR   GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR   GO; GO:0005829; C:cytosol; IEA:Ensembl.
DR   GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR   GO; GO:0005886; C:plasma membrane; IEA:Ensembl.
DR   GO; GO:0031685; F:adenosine receptor binding; ISO:RGD.
DR   GO; GO:0004843; F:cysteine-type deubiquitinase activity; ISS:UniProtKB.
DR   GO; GO:0042802; F:identical protein binding; ISO:RGD.
DR   GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR   GO; GO:0031397; P:negative regulation of protein ubiquitination; ISS:UniProtKB.
DR   GO; GO:1904263; P:positive regulation of TORC1 signaling; ISS:UniProtKB.
DR   GO; GO:0016579; P:protein deubiquitination; ISS:UniProtKB.
DR   GO; GO:0034394; P:protein localization to cell surface; ISS:UniProtKB.
DR   GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR   GO; GO:0031647; P:regulation of protein stability; ISS:UniProtKB.
DR   GO; GO:0000244; P:spliceosomal tri-snRNP complex assembly; ISS:UniProtKB.
DR   CDD; cd02674; Peptidase_C19R; 1.
DR   Gene3D; 3.90.70.10; Cysteine proteinases; 2.
DR   Gene3D; 3.30.2230.10; DUSP-like; 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   PANTHER; PTHR21646; UBIQUITIN CARBOXYL-TERMINAL HYDROLASE; 1.
DR   PANTHER; PTHR21646:SF45; UBIQUITIN CARBOXYL-TERMINAL HYDROLASE 4; 1.
DR   Pfam; PF06337; DUSP; 1.
DR   Pfam; PF14836; Ubiquitin_3; 1.
DR   Pfam; PF00443; UCH; 1.
DR   SMART; SM00695; DUSP; 1.
DR   SUPFAM; SSF54001; Cysteine proteinases; 1.
DR   SUPFAM; SSF143791; DUSP-like; 1.
DR   PROSITE; PS51283; DUSP; 1.
DR   PROSITE; PS00972; USP_1; 1.
DR   PROSITE; PS00973; USP_2; 1.
DR   PROSITE; PS50235; USP_3; 1.
DR   Genevisible; B2GUZ1; RN.
PE   1: Evidence at protein level;
KW   Cytoplasm; Hydrolase; Metal-binding; Nucleus; Phosphoprotein; Protease;
KW   Reference proteome; Repeat; Thiol protease; Ubl conjugation;
KW   Ubl conjugation pathway; Zinc.
FT   CHAIN           1..961
FT                   /note="Ubiquitin carboxyl-terminal hydrolase 4"
FT                   /id="PRO_0000396806"
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..921
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          27..216
FT                   /note="Necessary for interaction with SART3"
FT                   /evidence="ECO:0000250|UniProtKB:Q13107"
FT   REGION          219..257
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:0000250|UniProtKB:Q13107"
FT   REGION          384..386
FT                   /note="Regulates ubiquitin dissociation"
FT                   /evidence="ECO:0000250|UniProtKB:Q13107"
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   REGION          485..773
FT                   /note="Interacts with DUSP and ubiquitin-like 1 domains and
FT                   is required for USP4 activation"
FT                   /evidence="ECO:0000250|UniProtKB:Q13107"
FT   REGION          641..700
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          924..961
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           765..770
FT                   /note="Nuclear localization signal"
FT                   /evidence="ECO:0000250|UniProtKB:P35123"
FT   COMPBIAS        221..257
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        311
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01035"
FT   ACT_SITE        879
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01035"
FT   BINDING         461
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /evidence="ECO:0000250|UniProtKB:Q13107"
FT   BINDING         464
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /evidence="ECO:0000250|UniProtKB:Q13107"
FT   BINDING         797
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /evidence="ECO:0000250|UniProtKB:Q13107"
FT   BINDING         800
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /evidence="ECO:0000250|UniProtKB:Q13107"
FT   MOD_RES         445
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q13107"
FT   MOD_RES         655
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:22673903"
FT   MOD_RES         674
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:22673903"
FT   MOD_RES         679
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P35123"
SQ   SEQUENCE   961 AA;  108373 MW;  D6DD975327451B9F CRC64;
     MAEGRGTHER PDVETQKTEL GALMGTTLQR GAQWYLIDSR WFKQWKKYVG FDSWDMYNVG
     EHNLFPGPID NSGLFSDPES QTLKEHLIDE LDYVLVPTEA WNKLLNWYGC VEGQQPIVRK
     VVEHGLFVKH CKVEVYLLEL KLCENSDPTN VLSCHFSKAD TIATIEKEMR KLFNIPAERE
     TRLWNKYMSN TYEQLSKLDN TIQDAGLYQG QVLVIEPQNE DGTWPRQTLQ SKSSTAPSRN
     FTTSSKPSAS PYSSMSASLI ANGDSTNSSG MHNSGVSRGG AGFSASYNCQ EPPSPHIQPG
     LCGLGNLGNT CFMNSALQCL SNTGPLTEYF LKDEYEAEIN RDNPLGMKGE IAEAYAELIK
     QMWSGRDTHV APRMFKTQVG RFAPQFSGYQ QQDSQELLAF ILDGLHEDLN RVKKKPYLEP
     KDANGRPDAV VAKEAWENHR LRNDSVIVDT FHGLFKSTLV CPECAKVSVT FDPFCYLTLP
     LPLKKDRIME VFLVPADPHC RPIQYRVTVP LMGAISDLCE ALSKLSGIAA ENMVVTDVYN
     HRFHKIFQMD EGLSHITPRD DIFVYEICTT PMDGSEYITL PVYFREKKSR PSSTSSGAVL
     YGQPLLVSVP KHRLTLESLY QAVCERISRY IKQPLPEEFL SSPLEPGACN GSRGSYEGDE
     EEMDHQEEGK EQLSEVEESG EDSQGGDPTE TTQKAKGPPR HKRLFTFSLV NSCGTADINS
     LATDGKLLKL NSRSTLAIDW DSETRSLYFD EQESEACEKH TSMSQPQKKK KAAIALRECI
     ELFTTMETLG EHDPWYCPTC KKHQQATKKF DLWSLPKILV VHLKRFSYNR YWRDKLDTVV
     EFPVRALNMS EFVCDRAARP YVYDLIAVSN HYGAMGVGHY TAYAKNRLNG KWYYFDDSSV
     SLASEDQIVT KAAYVLFYQR RDDECPSTSS PVSFPGSDGG AKLSSSQQDL GEEEAYTMDT
     N
//