ID   UBP26_HUMAN             Reviewed;         913 AA.
AC   Q9BXU7; B9WRT6; Q5H9H4;
DT   26-SEP-2001, integrated into UniProtKB/Swiss-Prot.
DT   01-JUN-2001, sequence version 1.
DT   27-MAR-2024, entry version 164.
DE   RecName: Full=Ubiquitin carboxyl-terminal hydrolase 26;
DE            EC=3.4.19.12 {ECO:0000269|PubMed:28839133};
DE   AltName: Full=Deubiquitinating enzyme 26;
DE   AltName: Full=Ubiquitin thioesterase 26;
DE   AltName: Full=Ubiquitin-specific-processing protease 26;
GN   Name=USP26 {ECO:0000312|HGNC:HGNC:13485};
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].
RC   TISSUE=Testis;
RX   PubMed=11279525; DOI=10.1038/86927;
RA   Wang P.J., McCarrey J.R., Yang F., Page D.C.;
RT   "An abundance of X-linked genes expressed in spermatogonia.";
RL   Nat. Genet. 27:422-426(2001).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=15772651; DOI=10.1038/nature03440;
RA   Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D.,
RA   Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A., Lovell F.L.,
RA   Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G., Jones M.C.,
RA   Hurles M.E., Andrews T.D., Scott C.E., Searle S., Ramser J., Whittaker A.,
RA   Deadman R., Carter N.P., Hunt S.E., Chen R., Cree A., Gunaratne P.,
RA   Havlak P., Hodgson A., Metzker M.L., Richards S., Scott G., Steffen D.,
RA   Sodergren E., Wheeler D.A., Worley K.C., Ainscough R., Ambrose K.D.,
RA   Ansari-Lari M.A., Aradhya S., Ashwell R.I., Babbage A.K., Bagguley C.L.,
RA   Ballabio A., Banerjee R., Barker G.E., Barlow K.F., Barrett I.P.,
RA   Bates K.N., Beare D.M., Beasley H., Beasley O., Beck A., Bethel G.,
RA   Blechschmidt K., Brady N., Bray-Allen S., Bridgeman A.M., Brown A.J.,
RA   Brown M.J., Bonnin D., Bruford E.A., Buhay C., Burch P., Burford D.,
RA   Burgess J., Burrill W., Burton J., Bye J.M., Carder C., Carrel L.,
RA   Chako J., Chapman J.C., Chavez D., Chen E., Chen G., Chen Y., Chen Z.,
RA   Chinault C., Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA   Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S.,
RA   Corby N., Connor R.E., David R., Davies J., Davis C., Davis J., Delgado O.,
RA   Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S., Draper H.,
RA   Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I., Eades T.,
RA   Ellwood M., Emery-Cohen A., Errington H., Evans K.L., Faulkner L.,
RA   Francis F., Frankland J., Fraser A.E., Galgoczy P., Gilbert J., Gill R.,
RA   Gloeckner G., Gregory S.G., Gribble S., Griffiths C., Grocock R., Gu Y.,
RA   Gwilliam R., Hamilton C., Hart E.A., Hawes A., Heath P.D., Heitmann K.,
RA   Hennig S., Hernandez J., Hinzmann B., Ho S., Hoffs M., Howden P.J.,
RA   Huckle E.J., Hume J., Hunt P.J., Hunt A.R., Isherwood J., Jacob L.,
RA   Johnson D., Jones S., de Jong P.J., Joseph S.S., Keenan S., Kelly S.,
RA   Kershaw J.K., Khan Z., Kioschis P., Klages S., Knights A.J., Kosiura A.,
RA   Kovar-Smith C., Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L.,
RA   Liu W., Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D.,
RA   Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H.,
RA   McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T., Milne S.,
RA   Miner G., Mistry S.L., Morgan M., Morris S., Mueller I., Mullikin J.C.,
RA   Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N., Okwuonu G., Palmer S.,
RA   Pandian R., Parker D., Parrish J., Pasternak S., Patel D., Pearce A.V.,
RA   Pearson D.M., Pelan S.E., Perez L., Porter K.M., Ramsey Y., Reichwald K.,
RA   Rhodes S., Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K.,
RA   Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D.,
RA   Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R.,
RA   Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T., Teague B.,
RA   Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S., Tromans A.C.,
RA   d'Urso M., Verduzco D., Villasana D., Waldron L., Wall M., Wang Q.,
RA   Warren J., Warry G.L., Wei X., West A., Whitehead S.L., Whiteley M.N.,
RA   Wilkinson J.E., Willey D.L., Williams G., Williams L., Williamson A.,
RA   Williamson H., Wilming L., Woodmansey R.L., Wray P.W., Yen J., Zhang J.,
RA   Zhou J., Zoghbi H., Zorilla S., Buck D., Reinhardt R., Poustka A.,
RA   Rosenthal A., Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F.,
RA   Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A., Nelson D.L.,
RA   Weinstock G., Sulston J.E., Durbin R.M., Hubbard T., Gibbs R.A., Beck S.,
RA   Rogers J., Bentley D.R.;
RT   "The DNA sequence of the human X chromosome.";
RL   Nature 434:325-337(2005).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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   [4]
RP   FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF CYS-304.
RX   PubMed=20501646; DOI=10.1158/1541-7786.mcr-09-0424;
RA   Dirac A.M., Bernards R.;
RT   "The deubiquitinating enzyme USP26 is a regulator of androgen receptor
RT   signaling.";
RL   Mol. Cancer Res. 8:844-854(2010).
RN   [5]
RP   FUNCTION, CATALYTIC ACTIVITY, INTERACTION WITH RING1, AND MUTAGENESIS OF
RP   CYS-304.
RX   PubMed=28839133; DOI=10.1038/s41467-017-00301-4;
RA   Ning B., Zhao W., Qian C., Liu P., Li Q., Li W., Wang R.F.;
RT   "USP26 functions as a negative regulator of cellular reprogramming by
RT   stabilising PRC1 complex components.";
RL   Nat. Commun. 8:349-349(2017).
RN   [6]
RP   INVOLVEMENT IN SPGFX6, VARIANTS SPGFX6 SER-799 AND GLY-825,
RP   CHARACTERIZATION OF VARIANTS SPGFX6 SER-799 AND GLY-825, FUNCTION,
RP   SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX   PubMed=34202084; DOI=10.3390/cells10071594;
RA   Liu C., Shen Y., Shen Q., Zhang W., Wang J., Tang S., Wu H., Tian S.,
RA   Cong J., He X., Jin L., Zhang F., Jiang X., Cao Y.;
RT   "Novel Mutations in X-Linked, USP26-Induced Asthenoteratozoospermia and
RT   Male Infertility.";
RL   Cells 10:0-0(2021).
RN   [7]
RP   VARIANTS PHE-364 AND TYR-475.
RX   PubMed=15970005; DOI=10.1016/s1472-6483(10)61119-4;
RA   Paduch D.A., Mielnik A., Schlegel P.N.;
RT   "Novel mutations in testis-specific ubiquitin protease 26 gene may cause
RT   male infertility and hypogonadism.";
RL   Reprod. BioMed. Online 10:747-754(2005).
RN   [8]
RP   VARIANTS PHE-364 AND PHE-517.
RX   PubMed=18377898; DOI=10.1016/j.fertnstert.2007.06.096;
RA   Christensen G.L., Griffin J., Carrell D.T.;
RT   "Sequence analysis of the X-linked USP26 gene in severe male factor
RT   infertility patients and fertile controls.";
RL   Fertil. Steril. 90:851-852(2008).
RN   [9]
RP   VARIANTS THR-123 INS; SER-165; PHE-364; TYR-475 AND ILE-579.
RX   PubMed=18927127; DOI=10.1093/humrep/den374;
RA   Ribarski I., Lehavi O., Yogev L., Hauser R., Bar-Shira Maymon B.,
RA   Botchan A., Paz G., Yavetz H., Kleiman S.E.;
RT   "USP26 gene variations in fertile and infertile men.";
RL   Hum. Reprod. 24:477-484(2009).
CC   -!- FUNCTION: Deubiquitinase regulating several biological processes
CC       through the deubiquitination of components of these processes
CC       (PubMed:28839133, PubMed:20501646). Involved in somatic cell
CC       reprogramming through the 'Lys-48'-linked deubiquitination and
CC       stabilization of CBX4 and CBX6, two components of the polycomb-
CC       repressive complex 1 (PRC1) (PubMed:28839133). Also deubiquitinates and
CC       probably stabilizes the androgen receptor (AR), regulating the androgen
CC       receptor signaling pathway (PubMed:20501646). May play a role in
CC       spermatogenesis (PubMed:34202084). {ECO:0000269|PubMed:20501646,
CC       ECO:0000269|PubMed:28839133, ECO:0000269|PubMed:34202084}.
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:28839133};
CC   -!- SUBUNIT: Interacts with RING1. {ECO:0000269|PubMed:28839133}.
CC   -!- INTERACTION:
CC       Q9BXU7; P13569: CFTR; NbExp=4; IntAct=EBI-1641713, EBI-349854;
CC   -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:20501646}. Cytoplasm,
CC       cytoskeleton, flagellum axoneme {ECO:0000269|PubMed:34202084}.
CC   -!- TISSUE SPECIFICITY: Expressed in testis. {ECO:0000269|PubMed:34202084}.
CC   -!- DISEASE: Spermatogenic failure, X-linked, 6 (SPGFX6) [MIM:301101]: A
CC       male infertility disorder due to asthenoteratozoospermia and
CC       characterized by reduced progressive sperm motility and morphologic
CC       sperm abnormalities, such as thin heads and short or coiled flagella.
CC       {ECO:0000269|PubMed:34202084}. Note=The disease may be caused by
CC       variants affecting the gene represented in this entry.
CC   -!- SIMILARITY: Belongs to the peptidase C19 family. {ECO:0000305}.
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DR   EMBL; AF285593; AAK31972.1; -; mRNA.
DR   EMBL; Z81365; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; BC069073; AAH69073.1; -; mRNA.
DR   EMBL; BC101190; AAI01191.1; -; mRNA.
DR   EMBL; BC101191; AAI01192.1; -; mRNA.
DR   CCDS; CCDS14635.1; -.
DR   RefSeq; NP_114113.1; NM_031907.1.
DR   RefSeq; XP_016885381.1; XM_017029892.1.
DR   AlphaFoldDB; Q9BXU7; -.
DR   SMR; Q9BXU7; -.
DR   BioGRID; 123764; 21.
DR   IntAct; Q9BXU7; 4.
DR   MINT; Q9BXU7; -.
DR   STRING; 9606.ENSP00000423390; -.
DR   MEROPS; C19.046; -.
DR   GlyGen; Q9BXU7; 1 site, 1 O-linked glycan (1 site).
DR   iPTMnet; Q9BXU7; -.
DR   PhosphoSitePlus; Q9BXU7; -.
DR   BioMuta; USP26; -.
DR   DMDM; 18202739; -.
DR   MassIVE; Q9BXU7; -.
DR   PaxDb; 9606-ENSP00000423390; -.
DR   PeptideAtlas; Q9BXU7; -.
DR   ProteomicsDB; 79521; -.
DR   Antibodypedia; 30257; 120 antibodies from 22 providers.
DR   DNASU; 83844; -.
DR   Ensembl; ENST00000370832.1; ENSP00000359869.1; ENSG00000134588.13.
DR   Ensembl; ENST00000511190.6; ENSP00000423390.1; ENSG00000134588.13.
DR   GeneID; 83844; -.
DR   KEGG; hsa:83844; -.
DR   MANE-Select; ENST00000511190.6; ENSP00000423390.1; NM_031907.3; NP_114113.1.
DR   UCSC; uc010nrm.1; human.
DR   AGR; HGNC:13485; -.
DR   CTD; 83844; -.
DR   DisGeNET; 83844; -.
DR   GeneCards; USP26; -.
DR   HGNC; HGNC:13485; USP26.
DR   HPA; ENSG00000134588; Not detected.
DR   MalaCards; USP26; -.
DR   MIM; 300309; gene.
DR   MIM; 301101; phenotype.
DR   neXtProt; NX_Q9BXU7; -.
DR   OpenTargets; ENSG00000134588; -.
DR   PharmGKB; PA37782; -.
DR   VEuPathDB; HostDB:ENSG00000134588; -.
DR   eggNOG; KOG1868; Eukaryota.
DR   GeneTree; ENSGT00940000166393; -.
DR   HOGENOM; CLU_012557_0_0_1; -.
DR   InParanoid; Q9BXU7; -.
DR   OMA; NHLHLTF; -.
DR   OrthoDB; 227085at2759; -.
DR   PhylomeDB; Q9BXU7; -.
DR   TreeFam; TF323032; -.
DR   PathwayCommons; Q9BXU7; -.
DR   Reactome; R-HSA-5689880; Ub-specific processing proteases.
DR   SignaLink; Q9BXU7; -.
DR   BioGRID-ORCS; 83844; 17 hits in 815 CRISPR screens.
DR   GenomeRNAi; 83844; -.
DR   Pharos; Q9BXU7; Tbio.
DR   PRO; PR:Q9BXU7; -.
DR   Proteomes; UP000005640; Chromosome X.
DR   RNAct; Q9BXU7; Protein.
DR   Bgee; ENSG00000134588; Expressed in male germ line stem cell (sensu Vertebrata) in testis and 60 other cell types or tissues.
DR   GO; GO:0005856; C:cytoskeleton; IEA:UniProtKB-KW.
DR   GO; GO:0005829; C:cytosol; IDA:HPA.
DR   GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR   GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR   GO; GO:0036126; C:sperm flagellum; IMP:UniProtKB.
DR   GO; GO:0004843; F:cysteine-type deubiquitinase activity; IBA:GO_Central.
DR   GO; GO:0101005; F:deubiquitinase activity; IDA:UniProtKB.
DR   GO; GO:1990380; F:K48-linked deubiquitinase activity; IDA:UniProtKB.
DR   GO; GO:0000082; P:G1/S transition of mitotic cell cycle; IBA:GO_Central.
DR   GO; GO:0032435; P:negative regulation of proteasomal ubiquitin-dependent protein catabolic process; IMP:UniProtKB.
DR   GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR   GO; GO:0060765; P:regulation of androgen receptor signaling pathway; IMP:UniProtKB.
DR   GO; GO:0007283; P:spermatogenesis; IMP:UniProtKB.
DR   CDD; cd02257; Peptidase_C19; 2.
DR   CDD; cd13312; PH_USP37_like; 1.
DR   Gene3D; 3.90.70.10; Cysteine proteinases; 2.
DR   Gene3D; 2.30.29.180; Ubiquitin carboxyl-terminal hydrolase 26/29/37, pleckstrin homology-like domain; 1.
DR   InterPro; IPR038765; Papain-like_cys_pep_sf.
DR   InterPro; IPR001394; Peptidase_C19_UCH.
DR   InterPro; IPR032069; USP37-like_PH.
DR   InterPro; IPR038093; USP37-like_PH_sf.
DR   InterPro; IPR018200; USP_CS.
DR   InterPro; IPR028889; USP_dom.
DR   PANTHER; PTHR21646; UBIQUITIN CARBOXYL-TERMINAL HYDROLASE; 1.
DR   PANTHER; PTHR21646:SF23; UBIQUITIN CARBOXYL-TERMINAL HYDROLASE USP2; 1.
DR   Pfam; PF00443; UCH; 1.
DR   Pfam; PF16674; UCH_N; 1.
DR   SUPFAM; SSF54001; Cysteine proteinases; 1.
DR   PROSITE; PS00972; USP_1; 1.
DR   PROSITE; PS00973; USP_2; 1.
DR   PROSITE; PS50235; USP_3; 1.
DR   Genevisible; Q9BXU7; HS.
PE   1: Evidence at protein level;
KW   Cell projection; Cilium; Cytoplasm; Cytoskeleton; Flagellum; Hydrolase;
KW   Nucleus; Protease; Reference proteome; Thiol protease;
KW   Ubl conjugation pathway.
FT   CHAIN           1..913
FT                   /note="Ubiquitin carboxyl-terminal hydrolase 26"
FT                   /id="PRO_0000080655"
FT   DOMAIN          295..886
FT                   /note="USP"
FT   REGION          601..636
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          753..772
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        614..636
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        304
FT                   /note="Nucleophile"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10092,
FT                   ECO:0000255|PROSITE-ProRule:PRU10093"
FT   ACT_SITE        841
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10092,
FT                   ECO:0000255|PROSITE-ProRule:PRU10093"
FT   VARIANT         123
FT                   /note="T -> TT"
FT                   /evidence="ECO:0000269|PubMed:18927127"
FT                   /id="VAR_063413"
FT   VARIANT         165
FT                   /note="L -> S (in dbSNP:rs61741870)"
FT                   /evidence="ECO:0000269|PubMed:18927127"
FT                   /id="VAR_063414"
FT   VARIANT         364
FT                   /note="L -> F (in dbSNP:rs35397110)"
FT                   /evidence="ECO:0000269|PubMed:15970005,
FT                   ECO:0000269|PubMed:18377898, ECO:0000269|PubMed:18927127"
FT                   /id="VAR_063415"
FT   VARIANT         475
FT                   /note="H -> Y (in dbSNP:rs41299088)"
FT                   /evidence="ECO:0000269|PubMed:15970005,
FT                   ECO:0000269|PubMed:18927127"
FT                   /id="VAR_063416"
FT   VARIANT         517
FT                   /note="L -> F (in dbSNP:rs1323347016)"
FT                   /evidence="ECO:0000269|PubMed:18377898"
FT                   /id="VAR_063417"
FT   VARIANT         579
FT                   /note="M -> I (in dbSNP:rs138385391)"
FT                   /evidence="ECO:0000269|PubMed:18927127"
FT                   /id="VAR_063418"
FT   VARIANT         799
FT                   /note="N -> S (in SPGFX6; uncertain significance; decreased
FT                   protein abundance in patient sperm)"
FT                   /evidence="ECO:0000269|PubMed:34202084"
FT                   /id="VAR_088309"
FT   VARIANT         825
FT                   /note="R -> G (in SPGFX6; uncertain significance; decreased
FT                   protein abundance in patient sperm)"
FT                   /evidence="ECO:0000269|PubMed:34202084"
FT                   /id="VAR_088310"
FT   MUTAGEN         304
FT                   /note="C->S: Loss of deubiquitinase activity. Decreased
FT                   regulation of androgen receptor signaling pathway."
FT                   /evidence="ECO:0000269|PubMed:20501646,
FT                   ECO:0000269|PubMed:28839133"
SQ   SEQUENCE   913 AA;  104047 MW;  BB70B09CDCBA3C48 CRC64;
     MAALFLRGFV QIGNCKTGIS KSKEAFIEAV ERKKKDRLVL YFKSGKYSTF RLSDNIQNVV
     LKSYRGNQNH LHLTLQNNNG LFIEGLSSTD AEQLKIFLDR VHQNEVQPPV RPGKGGSVFS
     STTQKEINKT SFHKVDEKSS SKSFEIAKGS GTGVLQRMPL LTSKLTLTCG ELSENQHKKR
     KRMLSSSSEM NEEFLKENNS VEYKKSKADC SRCVSYNREK QLKLKELEEN KKLECESSCI
     MNATGNPYLD DIGLLQALTE KMVLVFLLQQ GYSDGYTKWD KLKLFFELFP EKICHGLPNL
     GNTCYMNAVL QSLLSIPSFA DDLLNQSFPW GKIPLNALTM CLARLLFFKD TYNIEIKEML
     LLNLKKAISA AAEIFHGNAQ NDAHEFLAHC LDQLKDNMEK LNTIWKPKSE FGEDNFPKQV
     FADDPDTSGF SCPVITNFEL ELLHSIACKA CGQVILKTEL NNYLSINLPQ RIKAHPSSIQ
     STFDLFFGAE ELEYKCAKCE HKTSVGVHSF SRLPRILIVH LKRYSLNEFC ALKKNDQEVI
     ISKYLKVSSH CNEGTRPPLP LSEDGEITDF QLLKVIRKMT SGNISVSWPA TKESKDILAP
     HIGSDKESEQ KKGQTVFKGA SRRQQQKYLG KNSKPNELES VYSGDRAFIE KEPLAHLMTY
     LEDTSLCQFH KAGGKPASSP GTPLSKVDFQ TVPENPKRKK YVKTSKFVAF DRIINPTKDL
     YEDKNIRIPE RFQKVSEQTQ QCDGMRICEQ APQQALPQSF PKPGTQGHTK NLLRPTKLNL
     QKSNRNSLLA LGSNKNPRNK DILDKIKSKA KETKRNDDKG DHTYRLISVV SHLGKTLKSG
     HYICDAYDFE KQIWFTYDDM RVLGIQEAQM QEDRRCTGYI FFYMHNEIFE EMLKREENAQ
     LNSKEVEETL QKE
//