ID   UBP25_MOUSE             Reviewed;        1055 AA.
AC   P57080; Q80ZT9;
DT   01-DEC-2000, integrated into UniProtKB/Swiss-Prot.
DT   13-APR-2004, sequence version 2.
DT   27-MAR-2024, entry version 178.
DE   RecName: Full=Ubiquitin carboxyl-terminal hydrolase 25;
DE            EC=3.4.19.12;
DE   AltName: Full=Deubiquitinating enzyme 25;
DE   AltName: Full=Ubiquitin thioesterase 25;
DE   AltName: Full=Ubiquitin-specific-processing protease 25;
DE            Short=mUSP25;
GN   Name=Usp25;
OS   Mus musculus (Mouse).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC   Murinae; Mus; Mus.
OX   NCBI_TaxID=10090;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA], DEVELOPMENTAL STAGE, AND TISSUE SPECIFICITY.
RC   TISSUE=Kidney;
RX   PubMed=10644437; DOI=10.1006/geno.1999.6025;
RA   Valero R., Marfany G., Gonzalez-Angulo O., Gonzalez-Gonzalez G.,
RA   Puelles L., Gonzalez-Duarte R.;
RT   "USP25, a novel gene encoding a deubiquitinating enzyme, is located in the
RT   gene-poor region 21q11.2.";
RL   Genomics 62:395-405(1999).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   STRAIN=C57BL/6J; 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   [3]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Brain, Brown adipose tissue, Heart, Kidney, Liver, Lung,
RC   Spleen, and Testis;
RX   PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA   Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA   Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT   "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL   Cell 143:1174-1189(2010).
RN   [4]
RP   STRUCTURE BY NMR OF 1-67.
RG   RIKEN structural genomics initiative (RSGI);
RT   "Solution structure of RSGI RUH-013, a UBA domain in mouse.";
RL   Submitted (SEP-2004) to the PDB data bank.
RN   [5]
RP   ALTERNATIVE SPLICING, DEVELOPMENTAL STAGE, POSSIBLE FUNCTION, AND
RP   SUBCELLULAR LOCATION.
RX   PubMed=16501887; DOI=10.1007/s00018-005-5533-1;
RA   Bosch-Comas A., Lindsten K., Gonzalez-Duarte R., Masucci M.G., Marfany G.;
RT   "The ubiquitin-specific protease USP25 interacts with three sarcomeric
RT   proteins.";
RL   Cell. Mol. Life Sci. 63:723-734(2006).
RN   [6]
RP   INDUCTION.
RX   PubMed=27129230; DOI=10.1074/jbc.m116.718080;
RA   Ren Y., Zhao Y., Lin D., Xu X., Zhu Q., Yao J., Shu H.B., Zhong B.;
RT   "The Type I Interferon-IRF7 Axis Mediates Transcriptional Expression of
RT   Usp25 Gene.";
RL   J. Biol. Chem. 291:13206-13215(2016).
RN   [7]
RP   FUNCTION, AND DISRUPTION PHENOTYPE.
RX   PubMed=26305951; DOI=10.1073/pnas.1509968112;
RA   Lin D., Zhang M., Zhang M.X., Ren Y., Jin J., Zhao Q., Pan Z., Wu M.,
RA   Shu H.B., Dong C., Zhong B.;
RT   "Induction of USP25 by viral infection promotes innate antiviral responses
RT   by mediating the stabilization of TRAF3 and TRAF6.";
RL   Proc. Natl. Acad. Sci. U.S.A. 112:11324-11329(2015).
RN   [8]
RP   FUNCTION, AND DISRUPTION PHENOTYPE.
RX   PubMed=37339955; DOI=10.1038/s41467-023-39412-6;
RA   Cai C., Ma H., Peng J., Shen X., Zhen X., Yu C., Zhang P., Ji F., Wang J.;
RT   "USP25 regulates KEAP1-NRF2 anti-oxidation axis and its inactivation
RT   protects acetaminophen-induced liver injury in male mice.";
RL   Nat. Commun. 14:3648-3648(2023).
CC   -!- FUNCTION: Deubiquitinating enzyme that hydrolyzes ubiquitin moieties
CC       conjugated to substrates and thus, functions in various biological
CC       processes including inflammation, immune response. Modulates the
CC       Wnt/beta-catenin pathway by deubiquitinating and stabilizing tankyrases
CC       TNKS1 and TNKS2. Regulates KEAP1-NRF2 axis in the defense against
CC       oxidative assaults by deubiquitinating KEAP1 and protecting it from
CC       degradation leading to degradation of the NRF2 transcription factor
CC       that is responsible for mounting an anti-oxidation gene expression
CC       program. Positively regulates RNA virus-induced innate signaling by
CC       interacting with and deubiquitinating ERLIN1 and ERLIN2. In turn,
CC       restricts virus production by regulating cholesterol biosynthetic flux.
CC       Acts as a negative regulator of interleukin-17-mediated signaling and
CC       inflammation through the removal of 'Lys-63'-linked ubiquitination of
CC       TRAF5 and TRAF6. Prevents the ubiquitination and degradation of TRAF3
CC       to reduce the phosphorylation levels of JNK and P38, the secretion of
CC       IL-1B and to induce endotoxin tolerance.
CC       {ECO:0000250|UniProtKB:Q9UHP3}.
CC   -!- FUNCTION: The muscle-specific isoform (USP25m) may have a role in the
CC       regulation of muscular differentiation and function.
CC       {ECO:0000250|UniProtKB:Q9UHP3}.
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:Q9UHP3};
CC   -!- SUBUNIT: Homotetramer, inhibited form. Homodimer, active form.
CC       Interacts with ACTA1 (via its C-terminus); the interaction occurs for
CC       all isoforms but is strongest for isoform USP25m in muscle
CC       differentiating cells. Interacts (isoform USP25m only) with MYBPC1; the
CC       interaction prevents proteasomal degradation of MYBPC1. Interacts
CC       (isoform USP25m only) with FLNC (via filament repeats 17-18, 20-21 and
CC       24). Interacts with GAPDH. Interacts with SUMO3; the interaction
CC       sumoylates efficiently USP25. Interacts with SUMO2; the interaction
CC       sumoylates efficiently USP25. Interacts with SUMO1; the interaction
CC       only weakly sumoylates USP25. Interacts with SYK; phosphorylates USP25
CC       and regulates USP25 intracellular levels.
CC       {ECO:0000250|UniProtKB:Q9UHP3}.
CC   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:16501887}. Nucleus
CC       {ECO:0000269|PubMed:16501887}. Note=The longer muscle-specific isoform
CC       (USP25m) Some transient punctuate nuclear location in myotubes during
CC       myocyte development.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=1;
CC         Comment=A longer muscle-specific isoform, USP25m, also exists.;
CC       Name=1;
CC         IsoId=P57080-1; Sequence=Displayed;
CC   -!- TISSUE SPECIFICITY: Highly expressed in testis especially in primary
CC       and secondary spematocytes and in immature spermatids. Also found in
CC       brain, skeletal muscle, liver and heart. {ECO:0000269|PubMed:10644437}.
CC   -!- DEVELOPMENTAL STAGE: At 13.5 dpc and 16.5 dpc, expression in the brain
CC       correlates with the proliferate ventricular zone and post-mitotic
CC       neurons of the intermediate zone, particularly in the forebrain. More
CC       marked expression at 16.5 dpc in the telencephalic septum and in the
CC       pallium. In myocytes, expressed throughout differentiation of myotubes.
CC       {ECO:0000269|PubMed:10644437, ECO:0000269|PubMed:16501887}.
CC   -!- INDUCTION: Induced by type I interferons (IFNA and IFNB1) produced in
CC       response to lipopolysaccharide (LPS) and viral infection (HIV-1 and SeV
CC       viruses) (at protein level). {ECO:0000269|PubMed:27129230}.
CC   -!- PTM: Acetylated. {ECO:0000250}.
CC   -!- PTM: Sumoylation impairs binding to and hydrolysis of ubiquitin chains.
CC       Sumoylated preferentially with SUMO2 or SUMO3. Desumoylated by SENP1.
CC       Regulated by ubiquitination on the same residue (By similarity).
CC       {ECO:0000250}.
CC   -!- PTM: Preferentially monoubiquitinated but can also be
CC       polyubiquitinated. Autodeubiquitinated. Ubiquitination activates the
CC       enzymatic activity either by preventing sumoylation or by allowing
CC       novel interactions (By similarity). {ECO:0000250}.
CC   -!- PTM: Phosphorylation in the C-terminal by SYK regulates USP25 cellular
CC       levels. {ECO:0000250}.
CC   -!- DISRUPTION PHENOTYPE: USP25-deficient mice are more susceptible to
CC       various viral infections including H5N1 or HHV-1 compared with the
CC       wild-type mice (PubMed:26305951). In addition, loss of USP25 protects
CC       the liver from oxidative stress-induced injury (PubMed:37339955).
CC       {ECO:0000269|PubMed:26305951, ECO:0000269|PubMed:37339955}.
CC   -!- SIMILARITY: Belongs to the peptidase C19 family. {ECO:0000305}.
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DR   EMBL; AF170563; AAF32264.1; -; mRNA.
DR   EMBL; BC048171; AAH48171.1; -; mRNA.
DR   EMBL; BC063059; AAH63059.1; -; mRNA.
DR   CCDS; CCDS28275.1; -. [P57080-1]
DR   RefSeq; NP_038946.2; NM_013918.2. [P57080-1]
DR   PDB; 1VDL; NMR; -; A=1-67.
DR   PDBsum; 1VDL; -.
DR   AlphaFoldDB; P57080; -.
DR   BMRB; P57080; -.
DR   SMR; P57080; -.
DR   BioGRID; 206017; 5.
DR   IntAct; P57080; 2.
DR   STRING; 10090.ENSMUSP00000023580; -.
DR   MEROPS; C19.041; -.
DR   iPTMnet; P57080; -.
DR   PhosphoSitePlus; P57080; -.
DR   EPD; P57080; -.
DR   MaxQB; P57080; -.
DR   PaxDb; 10090-ENSMUSP00000023580; -.
DR   PeptideAtlas; P57080; -.
DR   ProteomicsDB; 297794; -. [P57080-1]
DR   Pumba; P57080; -.
DR   Antibodypedia; 5805; 289 antibodies from 30 providers.
DR   DNASU; 30940; -.
DR   Ensembl; ENSMUST00000023580.8; ENSMUSP00000023580.7; ENSMUSG00000022867.12. [P57080-1]
DR   GeneID; 30940; -.
DR   KEGG; mmu:30940; -.
DR   UCSC; uc007zsb.1; mouse. [P57080-1]
DR   AGR; MGI:1353655; -.
DR   CTD; 29761; -.
DR   MGI; MGI:1353655; Usp25.
DR   VEuPathDB; HostDB:ENSMUSG00000022867; -.
DR   eggNOG; KOG1863; Eukaryota.
DR   GeneTree; ENSGT00940000157962; -.
DR   HOGENOM; CLU_012188_0_0_1; -.
DR   InParanoid; P57080; -.
DR   OrthoDB; 1423057at2759; -.
DR   PhylomeDB; P57080; -.
DR   TreeFam; TF329035; -.
DR   Reactome; R-MMU-5689880; Ub-specific processing proteases.
DR   BioGRID-ORCS; 30940; 0 hits in 77 CRISPR screens.
DR   ChiTaRS; Usp25; mouse.
DR   EvolutionaryTrace; P57080; -.
DR   PRO; PR:P57080; -.
DR   Proteomes; UP000000589; Chromosome 16.
DR   RNAct; P57080; Protein.
DR   Bgee; ENSMUSG00000022867; Expressed in hindlimb stylopod muscle and 261 other cell types or tissues.
DR   ExpressionAtlas; P57080; baseline and differential.
DR   GO; GO:0005829; C:cytosol; ISO:MGI.
DR   GO; GO:0005783; C:endoplasmic reticulum; ISO:MGI.
DR   GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR   GO; GO:0000502; C:proteasome complex; ISS:MGI.
DR   GO; GO:0051117; F:ATPase binding; ISO:MGI.
DR   GO; GO:0004843; F:cysteine-type deubiquitinase activity; ISS:MGI.
DR   GO; GO:0032183; F:SUMO binding; ISO:MGI.
DR   GO; GO:0031625; F:ubiquitin protein ligase binding; ISO:MGI.
DR   GO; GO:0006955; P:immune response; IMP:MGI.
DR   GO; GO:0097400; P:interleukin-17-mediated signaling pathway; IDA:MGI.
DR   GO; GO:0016071; P:mRNA metabolic process; IMP:MGI.
DR   GO; GO:1904293; P:negative regulation of ERAD pathway; ISO:MGI.
DR   GO; GO:0031647; P:regulation of protein stability; IBA:GO_Central.
DR   GO; GO:0006979; P:response to oxidative stress; IMP:MGI.
DR   GO; GO:0031098; P:stress-activated protein kinase signaling cascade; IMP:MGI.
DR   GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; ISS:MGI.
DR   CDD; cd02665; Peptidase_C19I; 1.
DR   CDD; cd14354; UBA_UBP25; 1.
DR   CDD; cd20486; USP25_C; 1.
DR   Gene3D; 6.10.250.1720; -; 1.
DR   Gene3D; 3.90.70.10; Cysteine proteinases; 1.
DR   Gene3D; 1.10.8.10; DNA helicase RuvA subunit, C-terminal domain; 1.
DR   InterPro; IPR038765; Papain-like_cys_pep_sf.
DR   InterPro; IPR001394; Peptidase_C19_UCH.
DR   InterPro; IPR009060; UBA-like_sf.
DR   InterPro; IPR003903; UIM_dom.
DR   InterPro; IPR018200; USP_CS.
DR   InterPro; IPR028889; USP_dom.
DR   PANTHER; PTHR24006; UBIQUITIN CARBOXYL-TERMINAL HYDROLASE; 1.
DR   PANTHER; PTHR24006:SF666; UBIQUITIN CARBOXYL-TERMINAL HYDROLASE 25; 1.
DR   Pfam; PF00443; UCH; 1.
DR   Pfam; PF02809; UIM; 2.
DR   SMART; SM00726; UIM; 1.
DR   SUPFAM; SSF54001; Cysteine proteinases; 1.
DR   SUPFAM; SSF46934; UBA-like; 1.
DR   PROSITE; PS50330; UIM; 1.
DR   PROSITE; PS00972; USP_1; 1.
DR   PROSITE; PS00973; USP_2; 1.
DR   PROSITE; PS50235; USP_3; 1.
DR   Genevisible; P57080; MM.
PE   1: Evidence at protein level;
KW   3D-structure; Alternative splicing; Coiled coil; Cytoplasm; Hydrolase;
KW   Isopeptide bond; Nucleus; Phosphoprotein; Protease; Reference proteome;
KW   Repeat; Thiol protease; Ubl conjugation; Ubl conjugation pathway.
FT   CHAIN           1..1055
FT                   /note="Ubiquitin carboxyl-terminal hydrolase 25"
FT                   /id="PRO_0000080654"
FT   DOMAIN          14..57
FT                   /note="UBA-like"
FT   DOMAIN          97..116
FT                   /note="UIM 1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00213"
FT   DOMAIN          123..140
FT                   /note="UIM 2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00213"
FT   DOMAIN          169..658
FT                   /note="USP"
FT   REGION          77..102
FT                   /note="SUMO interaction domain (SIM)"
FT   REGION          464..509
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          728..747
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOTIF           89..95
FT                   /note="Required for SUMO paralog-specific binding"
FT   COMPBIAS        470..506
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        178
FT                   /note="Nucleophile"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10092,
FT                   ECO:0000255|PROSITE-ProRule:PRU10093"
FT   ACT_SITE        608
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10092,
FT                   ECO:0000255|PROSITE-ProRule:PRU10093"
FT   MOD_RES         85
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q9UHP3"
FT   MOD_RES         740
FT                   /note="Phosphotyrosine"
FT                   /evidence="ECO:0000250|UniProtKB:Q9UHP3"
FT   CROSSLNK        99
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in SUMO); alternate"
FT                   /evidence="ECO:0000250"
FT   CROSSLNK        99
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in ubiquitin); alternate"
FT                   /evidence="ECO:0000250|UniProtKB:Q9UHP3"
FT   CONFLICT        394
FT                   /note="E -> K (in Ref. 1; AAF32264)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        496
FT                   /note="P -> L (in Ref. 1; AAF32264)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        683
FT                   /note="P -> L (in Ref. 1; AAF32264)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        841
FT                   /note="H -> L (in Ref. 1; AAF32264)"
FT                   /evidence="ECO:0000305"
FT   HELIX           9..12
FT                   /evidence="ECO:0007829|PDB:1VDL"
FT   HELIX           17..27
FT                   /evidence="ECO:0007829|PDB:1VDL"
FT   HELIX           33..43
FT                   /evidence="ECO:0007829|PDB:1VDL"
FT   HELIX           47..55
FT                   /evidence="ECO:0007829|PDB:1VDL"
SQ   SEQUENCE   1055 AA;  121420 MW;  103E34EC3FA8A72B CRC64;
     MTVEQNVLQQ SAAQKHQQTF LNQLREITGI NDAQILQQAL KDSNGNLELA VAFLTAKNAK
     TPPQEETGYY QTALPGNDRY ISVGSQADAN VIDLTGDDKD DLQRAIALSL AESNRAFRET
     GITDEEQAIS RVLEASIAEN KACLKRTPIE VWRDSRNPYD RKRQEKAPVG LKNVGNTCWF
     SAVIQSLFNL LEFRRLVLNY KPPSNAQDLP RNQKEHRNLP FMRELRYLFA LLVGTKRKYV
     DPSRAVEILK DAFKSNDSQQ QDVSEFTHKL LDWLEDAFQM KAEEETDEEK PKNPMVELFY
     GRFLAMGVLE GKKFENTEMF GQYPLQVNGF KDLHECLEAA MIEGEIESLH SDNSGKSGQE
     HWFTELPPVL TFELSRFEFN QALGRPEKIH NKLEFPQVLY LDRYMHRNRE ITRIKREEIK
     RLKDYLTVLQ QRLERYLSYG SGPKRFPLVD VLQYALEFAS SKPVCTSPVD DIDASSSASG
     PLPSQSLPST TEQQGPCASD LPGSSSPASG AALPLRSVIH KPFTQSRIPP DLPMHPAPRH
     ITEEELCVLE SCLHRWRTEI ENDTRDLQES ISRIHRTIEL MYSDKSMIQV PYRLHAVLVH
     EGQANAGHYW AYIFDHRESR WMKYNDIAVT KSSWEELVRD SFGGYRNASA YCLMYIDDKA
     QFLIQEEFNK ETGQALVGME TLPPDLRDFV EEDNQRFEKE LEEWDTQLAQ RSLQEKLLAA
     PKLREAEASA TTAQAGGADY LEQPSRSDLS KHWKEETLRV IAKASHDLED KGPETVLQSA
     IKLEYSRLVK LAQEDTPPET DYRLHHVLVY FIQNQAPKKI IEKTLLEQFG DRNLSFDERC
     HNIMKVAQAK LEMIKPEEVN LEEYEEWHAD YKKFRETTMY LITGLENFQR ESYIDSLLFL
     LCAYQNNKEL LSKGPYRGHD GELISHYRRE CLLKLNEQAA ELFESGEDGD VNNGLIIMNE
     FIVPFLPLLL VDDMEEKDIL AVEDMRNRWC SYLGQEMEAN LQEKLTDFLP KLLDCSTEIK
     GFHEPPKLPS YSAHELCERF ARIMLSLSRT PADGR
//