ID UBP25_HUMAN Reviewed; 1055 AA. AC Q9UHP3; C0LSZ0; Q6DHZ9; Q9H9W1; DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot. DT 10-AUG-2010, sequence version 4. DT 27-MAR-2024, entry version 209. DE RecName: Full=Ubiquitin carboxyl-terminal hydrolase 25; DE EC=3.4.19.12 {ECO:0000269|PubMed:23042150, ECO:0000269|PubMed:37339955}; DE AltName: Full=Deubiquitinating enzyme 25; DE AltName: Full=USP on chromosome 21; DE AltName: Full=Ubiquitin thioesterase 25; DE AltName: Full=Ubiquitin-specific-processing protease 25; GN Name=USP25; Synonyms=USP21; 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] (ISOFORMS USP25A AND USP25B), AND TISSUE RP SPECIFICITY. RC TISSUE=Fetal brain; 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 [MRNA] (ISOFORM USP25A), AND FUNCTION. RX PubMed=10612803; RX DOI=10.1002/(sici)1098-2264(200002)27:2<153::aid-gcc6>3.3.co;2-1; RA Groet J., Ives J.H., Jones T.A., Danton M., Flomen R.H., Sheer D., RA Hrascan R., Pavelic K., Nizetic D.; RT "Narrowing of the region of allelic loss in 21q11-21 in squamous non-small RT cell lung carcinoma and cloning of a novel ubiquitin-specific protease gene RT from the deleted segment."; RL Genes Chromosomes Cancer 27:153-161(2000). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM USP25M). RA Valero R., Bosch-Comas A., Denuc A., Gonzalez-Duarte R., Marfany G.; RL Submitted (FEB-2009) to the EMBL/GenBank/DDBJ databases. RN [4] 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 [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM USP25A). RC TISSUE=Placenta; 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 [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 319-1055 (ISOFORM USP25A). 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 [7] RP ALTERNATIVE SPLICING, FUNCTION, AND TISSUE SPECIFICITY. RX PubMed=11597335; DOI=10.1186/gb-2001-2-10-research0043; RA Valero R., Bayes M., Francisca Sanchez-Font M., Gonzalez-Angulo O., RA Gonzalez-Duarte R., Marfany G.; RT "Characterization of alternatively spliced products and tissue-specific RT isoforms of USP28 and USP25."; RL Genome Biol. 2:RESEARCH0043.1-RESEARCH0043.10(2001). RN [8] RP ALTERNATIVE SPLICING, INTERACTION WITH ACTA1; FLNC; GAPDH AND MYBPC1, RP INDUCTION, SUBCELLULAR LOCATION, AND POSSIBLE FUNCTION. 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 [9] RP SUMOYLATION AT LYS-99, FUNCTION, INTERACTION WITH SUMO1; SUMO3 AND RP UBIQUITIN, IDENTIFICATION BY MASS SPECTROMETRY, AND MUTAGENESIS OF VAL-91; RP ILE-92 AND LYS-99. RX PubMed=18538659; DOI=10.1016/j.molcel.2008.03.021; RA Meulmeester E., Kunze M., Hsiao H.H., Urlaub H., Melchior F.; RT "Mechanism and consequences for paralog-specific sumoylation of ubiquitin- RT specific protease 25."; RL Mol. Cell 30:610-619(2008). RN [10] RP UBIQUITINATION AT LYS-99, DEUBIQUITINATION, ACTIVE SITE CYS-178, RP ACETYLATION, PHOSPHORYLATION, SUMOYLATION, FUNCTION, SUBCELLULAR LOCATION, RP SUBUNIT, AND MUTAGENESIS OF LYS-99 AND CYS-178. RX PubMed=19440361; DOI=10.1371/journal.pone.0005571; RA Denuc A., Bosch-Comas A., Gonzalez-Duarte R., Marfany G.; RT "The UBA-UIM domains of the USP25 regulate the enzyme ubiquitination state RT and modulate substrate recognition."; RL PLoS ONE 4:E5571-E5571(2009). RN [11] RP INTERACTION WITH SYK, PHOSPHORYLATION AT TYR-740, AND MUTAGENESIS OF RP TYR-740; THR-878; TYR-880 AND ILE-883. RX PubMed=19909739; DOI=10.1016/j.yexcr.2009.10.023; RA Cholay M., Reverdy C., Benarous R., Colland F., Daviet L.; RT "Functional interaction between the ubiquitin-specific protease 25 and the RT SYK tyrosine kinase."; RL Exp. Cell Res. 316:667-675(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 FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=23042150; DOI=10.1038/ni.2427; RA Zhong B., Liu X., Wang X., Chang S.H., Liu X., Wang A., Reynolds J.M., RA Dong C.; RT "Negative regulation of IL-17-mediated signaling and inflammation by the RT ubiquitin-specific protease USP25."; RL Nat. Immunol. 13:1110-1117(2012). RN [14] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-85, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [15] RP UBIQUITINATION BY SMURF1, AND FUNCTION. RX PubMed=29518389; DOI=10.1016/j.bbrc.2018.03.015; RA Qian G., Hu X., Li G., Ding Y., Zhu L., Zheng H., Li M., Li Z., Pan J., RA Li Y., Li G., Yang C., Liu Y., Xie Y., Lv H.; RT "Smurf1 restricts the antiviral function mediated by USP25 through RT promoting its ubiquitination and degradation."; RL Biochem. Biophys. Res. Commun. 498:537-543(2018). RN [16] RP FUNCTION. RX PubMed=30579117; DOI=10.1016/j.molimm.2018.12.017; RA Wen J., Bai H., Chen N., Zhang W., Zhu X., Li P., Gong J.; RT "USP25 promotes endotoxin tolerance via suppressing K48-linked RT ubiquitination and degradation of TRAF3 in Kupffer cells."; RL Mol. Immunol. 106:53-62(2019). RN [17] RP FUNCTION, MUTAGENESIS OF CYS-178, AND CATALYTIC ACTIVITY. 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). RN [18] RP FUNCTION, MUTAGENESIS OF CYS-178, AND CATALYTIC ACTIVITY. RX PubMed=37683630; DOI=10.1016/j.devcel.2023.08.013; RA Teo Q.W., Wong H.H., Heunis T., Stancheva V., Hachim A., Lv H., Siu L., RA Ho J., Lan Y., Mok C.K.P., Ulferts R., Sanyal S.; RT "Usp25-Erlin1/2 activity limits cholesterol flux to restrict virus RT infection."; RL Dev. Cell 58:2495-2509(2023). RN [19] {ECO:0007744|PDB:5GP7} RP X-RAY CRYSTALLOGRAPHY (1.50 ANGSTROMS) OF 1046-1055, FUNCTION, SUBCELLULAR RP LOCATION, AND MUTAGENESIS OF CYS-178. RX PubMed=28619731; DOI=10.1101/gad.300889.117; RA Xu D., Liu J., Fu T., Shan B., Qian L., Pan L., Yuan J.; RT "USP25 regulates Wnt signaling by controlling the stability of RT tankyrases."; RL Genes Dev. 31:1024-1035(2017). RN [20] {ECO:0007744|PDB:5O71} RP X-RAY CRYSTALLOGRAPHY (3.28 ANGSTROMS) OF 1-714, SUBUNIT, AND MUTAGENESIS RP OF CYS-178. RX PubMed=30478318; DOI=10.1038/s41467-018-07510-5; RA Liu B., Sureda-Gomez M., Zhen Y., Amador V., Reverter D.; RT "A quaternary tetramer assembly inhibits the deubiquitinating activity of RT USP25."; RL Nat. Commun. 9:4973-4973(2018). RN [21] {ECO:0007744|PDB:6H4J, ECO:0007744|PDB:6H4K} RP X-RAY CRYSTALLOGRAPHY (2.05 ANGSTROMS) OF 765-1055, FUNCTION, AND SUBUNIT. RX PubMed=30926243; DOI=10.1016/j.molcel.2019.02.029; RA Sauer F., Klemm T., Kollampally R.B., Tessmer I., Nair R.K., Popov N., RA Kisker C.; RT "Differential Oligomerization of the Deubiquitinases USP25 and USP28 RT Regulates Their Activities."; RL Mol. Cell 74:421-435(2019). CC -!- FUNCTION: Deubiquitinating enzyme that hydrolyzes ubiquitin moieties CC conjugated to substrates and thus, functions in various biological CC processes including inflammation, immune response (PubMed:29518389, CC PubMed:37683630). Modulates the Wnt/beta-catenin pathway by CC deubiquitinating and stabilizing tankyrases TNKS1 and TNKS2 CC (PubMed:28619731, PubMed:30926243). Regulates KEAP1-NRF2 axis in the CC defense against oxidative assaults by deubiquitinating KEAP1 and CC protecting it from degradation leading to degradation of the NRF2 CC transcription factor that is responsible for mounting an anti-oxidation CC gene expression program (PubMed:37339955). Positively regulates RNA CC virus-induced innate signaling by interacting with and deubiquitinating CC ERLIN1 and ERLIN2 (PubMed:37683630). In turn, restricts virus CC production by regulating cholesterol biosynthetic flux CC (PubMed:37683630). Acts as a negative regulator of interleukin-17- CC mediated signaling and inflammation through the removal of 'Lys-63'- CC linked ubiquitination of TRAF5 and TRAF6 (PubMed:23042150). Prevents CC the ubiquitination and degradation of TRAF3 to reduce the CC phosphorylation levels of JNK and P38, the secretion of IL-1B and to CC induce endotoxin tolerance (PubMed:30579117). CC {ECO:0000269|PubMed:23042150, ECO:0000269|PubMed:28619731, CC ECO:0000269|PubMed:29518389, ECO:0000269|PubMed:30579117, CC ECO:0000269|PubMed:30926243, ECO:0000269|PubMed:37339955, CC ECO:0000269|PubMed:37683630}. CC -!- FUNCTION: The muscle-specific isoform (USP25m) may have a role in the CC regulation of muscular differentiation and function. 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:23042150, CC ECO:0000269|PubMed:37339955}; CC -!- SUBUNIT: Homotetramer, inhibited form (PubMed:30478318, CC PubMed:30926243). Homodimer, active form (PubMed:30926243). Interacts CC with ACTA1 (via its C-terminus); the interaction occurs for all CC isoforms but is strongest for isoform USP25m in muscle differentiating CC cells. Interacts (isoform USP25m only) with MYBPC1; the interaction CC prevents proteasomal degradation of MYBPC1. Interacts (isoform USP25m CC only) with FLNC (via filament repeats 17-18, 20-21 and 24). Interacts CC with GAPDH. Interacts with SUMO3; the interaction sumoylates CC efficiently USP25. Interacts with SUMO2; the interaction sumoylates CC efficiently USP25. Interacts with SUMO1; the interaction only weakly CC sumoylates USP25. Interacts with SYK; phosphorylates USP25 and CC regulates USP25 intracellular levels. {ECO:0000269|PubMed:16501887, CC ECO:0000269|PubMed:18538659, ECO:0000269|PubMed:19440361, CC ECO:0000269|PubMed:19909739, ECO:0000269|PubMed:30478318}. CC -!- INTERACTION: CC Q9UHP3; O15481: MAGEB4; NbExp=3; IntAct=EBI-2513462, EBI-751857; CC Q9UHP3; Q9UJV3-2: MID2; NbExp=3; IntAct=EBI-2513462, EBI-10172526; CC Q9UHP3; P17612: PRKACA; NbExp=3; IntAct=EBI-2513462, EBI-476586; CC Q9UHP3; Q3MIT2: PUS10; NbExp=3; IntAct=EBI-2513462, EBI-11983583; CC Q9UHP3; P54725: RAD23A; NbExp=12; IntAct=EBI-2513462, EBI-746453; CC Q9UHP3; P54727: RAD23B; NbExp=5; IntAct=EBI-2513462, EBI-954531; CC Q9UHP3; P61956: SUMO2; NbExp=6; IntAct=EBI-2513462, EBI-473220; CC Q9UHP3; P43405: SYK; NbExp=8; IntAct=EBI-2513462, EBI-78302; CC Q9UHP3; P37173: TGFBR2; NbExp=3; IntAct=EBI-2513462, EBI-296151; CC Q9UHP3; Q9BTV4: TMEM43; NbExp=3; IntAct=EBI-2513462, EBI-721293; CC Q9UHP3; Q9H2K2: TNKS2; NbExp=2; IntAct=EBI-2513462, EBI-4398527; CC Q9UHP3; Q9BUY5: ZNF426; NbExp=3; IntAct=EBI-2513462, EBI-743265; CC Q9UHP3; PRO_0000449633 [P0DTD1]: rep; Xeno; NbExp=6; IntAct=EBI-2513462, EBI-25492395; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:16501887, CC ECO:0000269|PubMed:19440361, ECO:0000269|PubMed:28619731}. CC -!- SUBCELLULAR LOCATION: [Isoform USP25m]: Cytoplasm {ECO:0000250}. CC Nucleus {ECO:0000250}. Note=Some transient punctuate nuclear location CC in myotubes during myocyte development. {ECO:0000250}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=USP25a; CC IsoId=Q9UHP3-2; Sequence=Displayed; CC Name=USP25b; CC IsoId=Q9UHP3-1; Sequence=VSP_039632; CC Name=USP25m; Synonyms=Muscle-specific isoform; CC IsoId=Q9UHP3-3; Sequence=VSP_039631; CC -!- TISSUE SPECIFICITY: Isoform USP25a is found in most adult and fetal CC tissues; expression is moderately high in testis, pancreas, kidney, CC skeletal muscle, liver, lung, placenta, brain, heart, but very low in CC peripheral blood, colon, small intestine, ovary, prostate, thymus and CC spleen. Isoform USP25b is found in all tissues except heart and CC skeletal muscle. Isoform USP25m is heart and skeletal muscle specific. CC {ECO:0000269|PubMed:10644437, ECO:0000269|PubMed:11597335}. CC -!- INDUCTION: The muscle-specific isoform (USP25m) is up-regulated during CC myocyte differentiation. Levels increase up to 100-fold towards CC completion of differentiation. {ECO:0000269|PubMed:16501887}. CC -!- PTM: Acetylated. {ECO:0000269|PubMed:19440361}. CC -!- PTM: Sumoylation impairs binding to and hydrolysis of ubiquitin chains. CC Sumoylated preferentially with SUMO2 or SUMO3. Desumoylated by SENP1. CC Polyubiquitinated by SMURF1 by promoting the 'Lys-48'-linkage leading CC to proteasomal degradation (PubMed:29518389). CC {ECO:0000269|PubMed:19440361, ECO:0000269|PubMed:29518389}. 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. {ECO:0000269|PubMed:19440361}. CC -!- PTM: Phosphorylation in the C-terminal by SYK regulates USP25 cellular CC levels. {ECO:0000269|PubMed:19440361, ECO:0000269|PubMed:19909739}. CC -!- SIMILARITY: Belongs to the peptidase C19 family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF170562; AAF32263.1; -; mRNA. DR EMBL; AF134213; AAF24998.1; -; mRNA. DR EMBL; FJ763652; ACN76567.1; -; mRNA. DR EMBL; CH471079; EAX10041.1; -; Genomic_DNA. DR EMBL; BC075792; AAH75792.1; -; mRNA. DR EMBL; AK022574; BAB14107.1; -; mRNA. DR CCDS; CCDS33515.1; -. [Q9UHP3-2] DR CCDS; CCDS63336.1; -. [Q9UHP3-3] DR CCDS; CCDS63337.1; -. [Q9UHP3-1] DR RefSeq; NP_001269970.1; NM_001283041.1. [Q9UHP3-3] DR RefSeq; NP_001269971.1; NM_001283042.1. [Q9UHP3-1] DR RefSeq; NP_037528.3; NM_013396.4. [Q9UHP3-2] DR PDB; 2MUX; NMR; -; A=1-146. DR PDB; 5GP7; X-ray; 1.50 A; B=1046-1055. DR PDB; 5O71; X-ray; 3.28 A; A=1-714. DR PDB; 6H4J; X-ray; 3.07 A; A/B=157-706. DR PDB; 6H4K; X-ray; 2.05 A; A=765-1055. DR PDB; 6HEL; X-ray; 2.94 A; A/B=157-714. DR PDB; 6HEM; X-ray; 1.72 A; A=748-1048. DR PDBsum; 2MUX; -. DR PDBsum; 5GP7; -. DR PDBsum; 5O71; -. DR PDBsum; 6H4J; -. DR PDBsum; 6H4K; -. DR PDBsum; 6HEL; -. DR PDBsum; 6HEM; -. DR AlphaFoldDB; Q9UHP3; -. DR BMRB; Q9UHP3; -. DR SMR; Q9UHP3; -. DR BioGRID; 118895; 93. DR IntAct; Q9UHP3; 53. DR MINT; Q9UHP3; -. DR STRING; 9606.ENSP00000383044; -. DR BindingDB; Q9UHP3; -. DR ChEMBL; CHEMBL4295975; -. DR MEROPS; C19.041; -. DR iPTMnet; Q9UHP3; -. DR PhosphoSitePlus; Q9UHP3; -. DR BioMuta; USP25; -. DR DMDM; 302393833; -. DR EPD; Q9UHP3; -. DR jPOST; Q9UHP3; -. DR MassIVE; Q9UHP3; -. DR MaxQB; Q9UHP3; -. DR PaxDb; 9606-ENSP00000383044; -. DR PeptideAtlas; Q9UHP3; -. DR ProteomicsDB; 84385; -. [Q9UHP3-2] DR ProteomicsDB; 84386; -. [Q9UHP3-1] DR ProteomicsDB; 84387; -. [Q9UHP3-3] DR Pumba; Q9UHP3; -. DR Antibodypedia; 5805; 289 antibodies from 30 providers. DR DNASU; 29761; -. DR Ensembl; ENST00000285679.10; ENSP00000285679.6; ENSG00000155313.16. [Q9UHP3-2] DR Ensembl; ENST00000285681.6; ENSP00000285681.2; ENSG00000155313.16. [Q9UHP3-1] DR Ensembl; ENST00000400183.7; ENSP00000383044.2; ENSG00000155313.16. [Q9UHP3-3] DR GeneID; 29761; -. DR KEGG; hsa:29761; -. DR MANE-Select; ENST00000400183.7; ENSP00000383044.2; NM_001283041.3; NP_001269970.1. [Q9UHP3-3] DR UCSC; uc002yjy.3; human. [Q9UHP3-2] DR AGR; HGNC:12624; -. DR CTD; 29761; -. DR DisGeNET; 29761; -. DR GeneCards; USP25; -. DR HGNC; HGNC:12624; USP25. DR HPA; ENSG00000155313; Tissue enhanced (skeletal). DR MIM; 604736; gene. DR neXtProt; NX_Q9UHP3; -. DR OpenTargets; ENSG00000155313; -. DR PharmGKB; PA37249; -. DR VEuPathDB; HostDB:ENSG00000155313; -. DR eggNOG; KOG1863; Eukaryota. DR GeneTree; ENSGT00940000157962; -. DR HOGENOM; CLU_012188_0_0_1; -. DR InParanoid; Q9UHP3; -. DR OMA; XKKFENT; -. DR OrthoDB; 1423057at2759; -. DR PhylomeDB; Q9UHP3; -. DR TreeFam; TF329035; -. DR PathwayCommons; Q9UHP3; -. DR Reactome; R-HSA-5689880; Ub-specific processing proteases. DR SignaLink; Q9UHP3; -. DR SIGNOR; Q9UHP3; -. DR BioGRID-ORCS; 29761; 12 hits in 1206 CRISPR screens. DR ChiTaRS; USP25; human. DR GenomeRNAi; 29761; -. DR Pharos; Q9UHP3; Tchem. DR PRO; PR:Q9UHP3; -. DR Proteomes; UP000005640; Chromosome 21. DR RNAct; Q9UHP3; Protein. DR Bgee; ENSG00000155313; Expressed in sperm and 200 other cell types or tissues. DR ExpressionAtlas; Q9UHP3; baseline and differential. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:ParkinsonsUK-UCL. DR GO; GO:0005634; C:nucleus; IBA:GO_Central. DR GO; GO:0051117; F:ATPase binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0004843; F:cysteine-type deubiquitinase activity; IMP:UniProtKB. DR GO; GO:0008233; F:peptidase activity; TAS:ProtInc. DR GO; GO:0032183; F:SUMO binding; IPI:UniProtKB. DR GO; GO:0043130; F:ubiquitin binding; NAS:ParkinsonsUK-UCL. DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0019783; F:ubiquitin-like protein peptidase activity; NAS:ParkinsonsUK-UCL. DR GO; GO:1904293; P:negative regulation of ERAD pathway; IMP:ParkinsonsUK-UCL. DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IEA:InterPro. DR GO; GO:0016579; P:protein deubiquitination; IDA:ParkinsonsUK-UCL. DR GO; GO:0071108; P:protein K48-linked deubiquitination; IMP:UniProtKB. DR GO; GO:0070536; P:protein K63-linked deubiquitination; IMP:UniProtKB. DR GO; GO:0036211; P:protein modification process; TAS:ProtInc. DR GO; GO:0006508; P:proteolysis; TAS:ProtInc. DR GO; GO:0031647; P:regulation of protein stability; IBA:GO_Central. 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; IPR044635; UBP14-like. DR InterPro; IPR003903; UIM_dom. DR InterPro; IPR018200; USP_CS. DR InterPro; IPR028889; USP_dom. DR PANTHER; PTHR43982; UBIQUITIN CARBOXYL-TERMINAL HYDROLASE; 1. DR PANTHER; PTHR43982:SF6; UBIQUITIN CARBOXYL-TERMINAL HYDROLASE 2-RELATED; 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; Q9UHP3; HS. 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_0000080653" 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..657 FT /note="USP" FT REGION 77..102 FT /note="SUMO interaction domain (SIM)" FT REGION 464..507 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 727..749 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COILED 541..578 FT /evidence="ECO:0000255" FT COILED 684..717 FT /evidence="ECO:0000255" FT MOTIF 89..95 FT /note="Required for SUMO paralog-specific binding" FT COMPBIAS 472..507 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 178 FT /evidence="ECO:0000269|PubMed:19440361" FT ACT_SITE 599 FT /evidence="ECO:0000250" FT ACT_SITE 607 FT /evidence="ECO:0000250" FT MOD_RES 85 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 740 FT /note="Phosphotyrosine" FT /evidence="ECO:0000269|PubMed:19909739" FT CROSSLNK 99 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO); alternate" FT CROSSLNK 99 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin); alternate" FT /evidence="ECO:0000269|PubMed:19440361" FT VAR_SEQ 779 FT /note="S -> SIMMTPNMQGIIMAIGKSRSVYDRCGPEAGFFK (in isoform FT USP25b)" FT /evidence="ECO:0000303|PubMed:10644437" FT /id="VSP_039632" FT VAR_SEQ 779 FT /note="S -> SKPENTTSQPLSNQRVVEVAIPHVGKFMIESKEGGYDDEIMMTPNMQ FT GIIMAIGKSRSVYDRCGPEAGFFK (in isoform USP25m)" FT /evidence="ECO:0000303|Ref.3" FT /id="VSP_039631" FT MUTAGEN 91 FT /note="V->A: No interaction with SUMO3; when associated FT with A-92." FT /evidence="ECO:0000269|PubMed:18538659" FT MUTAGEN 92 FT /note="I->A: No interaction with SUMO3; when associated FT with A-91." FT /evidence="ECO:0000269|PubMed:18538659" FT MUTAGEN 99 FT /note="K->R: Abolishes sumoylation. Decreased enzymatic FT activity." FT /evidence="ECO:0000269|PubMed:18538659, FT ECO:0000269|PubMed:19440361" FT MUTAGEN 178 FT /note="C->S: Abrogates deubiquitinating activity. No effect FT on homo- or oligomerization." FT /evidence="ECO:0000269|PubMed:19440361, FT ECO:0000269|PubMed:28619731, ECO:0000269|PubMed:30478318, FT ECO:0000269|PubMed:37339955" FT MUTAGEN 740 FT /note="Y->F: No effect on interaction with SYK." FT /evidence="ECO:0000269|PubMed:19909739" FT MUTAGEN 878 FT /note="T->I: No effect on interaction with SYK." FT /evidence="ECO:0000269|PubMed:19909739" FT MUTAGEN 880 FT /note="Y->F: No effect on interaction with SYK." FT /evidence="ECO:0000269|PubMed:19909739" FT MUTAGEN 883 FT /note="I->S: No effect on interaction with SYK." FT /evidence="ECO:0000269|PubMed:19909739" FT CONFLICT 544 FT /note="E -> K (in Ref. 1; AAF32263 and 3; ACN76567)" FT /evidence="ECO:0000305" FT HELIX 12..27 FT /evidence="ECO:0007829|PDB:2MUX" FT HELIX 33..43 FT /evidence="ECO:0007829|PDB:2MUX" FT HELIX 47..55 FT /evidence="ECO:0007829|PDB:2MUX" FT STRAND 61..64 FT /evidence="ECO:0007829|PDB:2MUX" FT STRAND 69..71 FT /evidence="ECO:0007829|PDB:2MUX" FT HELIX 100..116 FT /evidence="ECO:0007829|PDB:2MUX" FT HELIX 125..136 FT /evidence="ECO:0007829|PDB:2MUX" FT TURN 158..161 FT /evidence="ECO:0007829|PDB:6H4J" FT STRAND 164..166 FT /evidence="ECO:0007829|PDB:5O71" FT TURN 174..176 FT /evidence="ECO:0007829|PDB:6H4J" FT HELIX 178..189 FT /evidence="ECO:0007829|PDB:6HEL" FT HELIX 191..198 FT /evidence="ECO:0007829|PDB:6HEL" FT HELIX 218..234 FT /evidence="ECO:0007829|PDB:6HEL" FT STRAND 237..240 FT /evidence="ECO:0007829|PDB:6HEL" FT HELIX 243..248 FT /evidence="ECO:0007829|PDB:6HEL" FT HELIX 263..279 FT /evidence="ECO:0007829|PDB:6HEL" FT HELIX 283..285 FT /evidence="ECO:0007829|PDB:5O71" FT HELIX 294..299 FT /evidence="ECO:0007829|PDB:6HEL" FT STRAND 302..304 FT /evidence="ECO:0007829|PDB:6HEL" FT STRAND 309..311 FT /evidence="ECO:0007829|PDB:6HEL" FT STRAND 321..326 FT /evidence="ECO:0007829|PDB:6HEL" FT HELIX 333..342 FT /evidence="ECO:0007829|PDB:6HEL" FT STRAND 348..350 FT /evidence="ECO:0007829|PDB:6H4J" FT TURN 351..355 FT /evidence="ECO:0007829|PDB:6H4J" FT STRAND 362..365 FT /evidence="ECO:0007829|PDB:6HEL" FT STRAND 368..375 FT /evidence="ECO:0007829|PDB:6HEL" FT STRAND 377..380 FT /evidence="ECO:0007829|PDB:6HEL" FT TURN 381..384 FT /evidence="ECO:0007829|PDB:6HEL" FT STRAND 385..388 FT /evidence="ECO:0007829|PDB:6HEL" FT STRAND 397..400 FT /evidence="ECO:0007829|PDB:6HEL" FT TURN 402..404 FT /evidence="ECO:0007829|PDB:6HEL" FT HELIX 406..408 FT /evidence="ECO:0007829|PDB:6HEL" FT HELIX 409..437 FT /evidence="ECO:0007829|PDB:6HEL" FT STRAND 441..444 FT /evidence="ECO:0007829|PDB:6HEL" FT HELIX 448..460 FT /evidence="ECO:0007829|PDB:6HEL" FT STRAND 534..536 FT /evidence="ECO:0007829|PDB:6HEL" FT HELIX 542..579 FT /evidence="ECO:0007829|PDB:6HEL" FT HELIX 584..586 FT /evidence="ECO:0007829|PDB:6HEL" FT STRAND 590..601 FT /evidence="ECO:0007829|PDB:6HEL" FT STRAND 603..614 FT /evidence="ECO:0007829|PDB:6HEL" FT TURN 615..618 FT /evidence="ECO:0007829|PDB:6HEL" FT STRAND 619..624 FT /evidence="ECO:0007829|PDB:6HEL" FT STRAND 627..629 FT /evidence="ECO:0007829|PDB:6HEL" FT HELIX 633..640 FT /evidence="ECO:0007829|PDB:6HEL" FT STRAND 641..644 FT /evidence="ECO:0007829|PDB:6HEL" FT STRAND 648..658 FT /evidence="ECO:0007829|PDB:6HEL" FT HELIX 660..662 FT /evidence="ECO:0007829|PDB:6HEL" FT TURN 669..671 FT /evidence="ECO:0007829|PDB:6HEL" FT HELIX 677..680 FT /evidence="ECO:0007829|PDB:6HEL" FT HELIX 683..700 FT /evidence="ECO:0007829|PDB:6HEL" FT HELIX 751..765 FT /evidence="ECO:0007829|PDB:6HEM" FT HELIX 773..793 FT /evidence="ECO:0007829|PDB:6HEM" FT HELIX 802..804 FT /evidence="ECO:0007829|PDB:6HEM" FT HELIX 807..813 FT /evidence="ECO:0007829|PDB:6HEM" FT HELIX 818..829 FT /evidence="ECO:0007829|PDB:6HEM" FT HELIX 832..834 FT /evidence="ECO:0007829|PDB:6HEM" FT STRAND 835..837 FT /evidence="ECO:0007829|PDB:6HEM" FT TURN 838..840 FT /evidence="ECO:0007829|PDB:6HEM" FT HELIX 841..853 FT /evidence="ECO:0007829|PDB:6HEM" FT TURN 856..858 FT /evidence="ECO:0007829|PDB:6HEM" FT HELIX 861..889 FT /evidence="ECO:0007829|PDB:6HEM" FT HELIX 893..913 FT /evidence="ECO:0007829|PDB:6HEM" FT HELIX 921..943 FT /evidence="ECO:0007829|PDB:6HEM" FT HELIX 948..960 FT /evidence="ECO:0007829|PDB:6HEM" FT HELIX 962..965 FT /evidence="ECO:0007829|PDB:6HEM" FT HELIX 966..970 FT /evidence="ECO:0007829|PDB:6HEM" FT HELIX 976..990 FT /evidence="ECO:0007829|PDB:6HEM" FT HELIX 991..994 FT /evidence="ECO:0007829|PDB:6HEM" FT HELIX 999..1013 FT /evidence="ECO:0007829|PDB:6HEM" FT HELIX 1033..1044 FT /evidence="ECO:0007829|PDB:6HEM" SQ SEQUENCE 1055 AA; 122218 MW; 0B9CECDCAD619CF2 CRC64; MTVEQNVLQQ SAAQKHQQTF LNQLREITGI NDTQILQQAL KDSNGNLELA VAFLTAKNAK TPQQEETTYY QTALPGNDRY ISVGSQADTN VIDLTGDDKD DLQRAIALSL AESNRAFRET GITDEEQAIS RVLEASIAEN KACLKRTPTE VWRDSRNPYD RKRQDKAPVG LKNVGNTCWF SAVIQSLFNL LEFRRLVLNY KPPSNAQDLP RNQKEHRNLP FMRELRYLFA LLVGTKRKYV DPSRAVEILK DAFKSNDSQQ QDVSEFTHKL LDWLEDAFQM KAEEETDEEK PKNPMVELFY GRFLAVGVLE GKKFENTEMF GQYPLQVNGF KDLHECLEAA MIEGEIESLH SENSGKSGQE HWFTELPPVL TFELSRFEFN QALGRPEKIH NKLEFPQVLY LDRYMHRNRE ITRIKREEIK RLKDYLTVLQ QRLERYLSYG SGPKRFPLVD VLQYALEFAS SKPVCTSPVD DIDASSPPSG SIPSQTLPST TEQQGALSSE LPSTSPSSVA AISSRSVIHK PFTQSRIPPD LPMHPAPRHI TEEELSVLES CLHRWRTEIE NDTRDLQESI SRIHRTIELM YSDKSMIQVP YRLHAVLVHE GQANAGHYWA YIFDHRESRW MKYNDIAVTK SSWEELVRDS FGGYRNASAY CLMYINDKAQ FLIQEEFNKE TGQPLVGIET LPPDLRDFVE EDNQRFEKEL EEWDAQLAQK ALQEKLLASQ KLRESETSVT TAQAAGDPEY LEQPSRSDFS KHLKEETIQI ITKASHEHED KSPETVLQSA IKLEYARLVK LAQEDTPPET DYRLHHVVVY FIQNQAPKKI IEKTLLEQFG DRNLSFDERC HNIMKVAQAK LEMIKPEEVN LEEYEEWHQD YRKFRETTMY LIIGLENFQR ESYIDSLLFL ICAYQNNKEL LSKGLYRGHD EELISHYRRE CLLKLNEQAA ELFESGEDRE VNNGLIIMNE FIVPFLPLLL VDEMEEKDIL AVEDMRNRWC SYLGQEMEPH LQEKLTDFLP KLLDCSMEIK SFHEPPKLPS YSTHELCERF ARIMLSLSRT PADGR //