UBP27_HUMAN
ID UBP27_HUMAN Reviewed; 438 AA.
AC A6NNY8;
DT 02-OCT-2007, integrated into UniProtKB/Swiss-Prot.
DT 24-MAR-2009, sequence version 3.
DT 03-AUG-2022, entry version 112.
DE RecName: Full=Ubiquitin carboxyl-terminal hydrolase 27;
DE EC=3.4.19.12 {ECO:0000269|PubMed:31534008, ECO:0000269|PubMed:32027733};
DE AltName: Full=Deubiquitinating enzyme 27;
DE AltName: Full=Ubiquitin carboxyl-terminal hydrolase 22-like;
DE AltName: Full=Ubiquitin thioesterase 27;
DE AltName: Full=Ubiquitin-specific-processing protease 27;
DE AltName: Full=X-linked ubiquitin carboxyl-terminal hydrolase 27;
GN Name=USP27X {ECO:0000303|PubMed:31534008, ECO:0000312|HGNC:HGNC:13486};
GN Synonyms=USP22L, USP27;
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 [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 [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-45.
RC TISSUE=Placenta;
RA Birkett C., Cho J., Gau Y., Hamer R., Kelly S., Kovacs K., Liu L., Liu X.,
RA Porter J., Sachs A., Shu Y., Sun Z., Wong J., Wu M., Zhang X., Jay G.,
RA He W.;
RT "High-throughput cloning of full-length human cDNAs directly from cDNA
RT libraries optimized for large and rare transcripts.";
RL Submitted (MAY-2005) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP IDENTIFICATION.
RX PubMed=12838346; DOI=10.1038/nrg1111;
RA Puente X.S., Sanchez L.M., Overall C.M., Lopez-Otin C.;
RT "Human and mouse proteases: a comparative genomic approach.";
RL Nat. Rev. Genet. 4:544-558(2003).
RN [4]
RP INVOLVEMENT IN XLID105, AND VARIANT XLID105 HIS-381.
RX PubMed=25644381; DOI=10.1038/mp.2014.193;
RA Hu H., Haas S.A., Chelly J., Van Esch H., Raynaud M., de Brouwer A.P.,
RA Weinert S., Froyen G., Frints S.G., Laumonnier F., Zemojtel T., Love M.I.,
RA Richard H., Emde A.K., Bienek M., Jensen C., Hambrock M., Fischer U.,
RA Langnick C., Feldkamp M., Wissink-Lindhout W., Lebrun N., Castelnau L.,
RA Rucci J., Montjean R., Dorseuil O., Billuart P., Stuhlmann T., Shaw M.,
RA Corbett M.A., Gardner A., Willis-Owen S., Tan C., Friend K.L., Belet S.,
RA van Roozendaal K.E., Jimenez-Pocquet M., Moizard M.P., Ronce N., Sun R.,
RA O'Keeffe S., Chenna R., van Boemmel A., Goeke J., Hackett A., Field M.,
RA Christie L., Boyle J., Haan E., Nelson J., Turner G., Baynam G.,
RA Gillessen-Kaesbach G., Mueller U., Steinberger D., Budny B.,
RA Badura-Stronka M., Latos-Bielenska A., Ousager L.B., Wieacker P.,
RA Rodriguez Criado G., Bondeson M.L., Anneren G., Dufke A., Cohen M.,
RA Van Maldergem L., Vincent-Delorme C., Echenne B., Simon-Bouy B.,
RA Kleefstra T., Willemsen M., Fryns J.P., Devriendt K., Ullmann R.,
RA Vingron M., Wrogemann K., Wienker T.F., Tzschach A., van Bokhoven H.,
RA Gecz J., Jentsch T.J., Chen W., Ropers H.H., Kalscheuer V.M.;
RT "X-exome sequencing of 405 unresolved families identifies seven novel
RT intellectual disability genes.";
RL Mol. Psychiatry 21:133-148(2016).
RN [5]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVE SITE, AND MUTAGENESIS OF CYS-87.
RX PubMed=31534008; DOI=10.4049/jimmunol.1900514;
RA Guo Y., Jiang F., Kong L., Li B., Yang Y., Zhang L., Liu B., Zheng Y.,
RA Gao C.;
RT "USP27X deubiquitinates and stabilizes the DNA sensor cGAS to regulate
RT cytosolic DNA-mediated signaling.";
RL J. Immunol. 203:2049-2054(2019).
RN [6]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVE SITES, AND MUTAGENESIS OF CYS-87 AND
RP HIS-380.
RX PubMed=32027733; DOI=10.1371/journal.ppat.1008293;
RA Tao X., Chu B., Xin D., Li L., Sun Q.;
RT "USP27X negatively regulates antiviral signaling by deubiquitinating RIG-
RT I.";
RL PLoS Pathog. 16:e1008293-e1008293(2020).
CC -!- FUNCTION: Deubiquitinase involved in innate antiviral immunity by
CC mediating deubiquitination of CGAS and DDX58/RIG-I (PubMed:31534008,
CC PubMed:32027733). Negatively regulates DDX58/RIG-I by mediating 'Lys-
CC 63'-linked deubiquitination of DDX58/RIG-I, inhibiting type I
CC interferon signaling (PubMed:32027733). Also regulates 'Lys-63'-linked
CC ubiquitination level of MDA5/IFIH1 (PubMed:32027733). Acts as a
CC positive regulator of the cGAS-STING pathway by catalyzing 'Lys-48'-
CC linked deubiquitination of CGAS, thereby promoting its stabilization
CC (PubMed:31534008). Can reduce the levels of BCL2L11/BIM ubiquitination
CC and stabilize BCL2L11 in response to the RAF-MAPK-degradation signal
CC (By similarity). By acting on BCL2L11 levels, may counteract the anti-
CC apoptotic effects of MAPK activity (By similarity).
CC {ECO:0000250|UniProtKB:Q8CEG8, ECO:0000269|PubMed:31534008,
CC ECO:0000269|PubMed:32027733}.
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:31534008,
CC ECO:0000269|PubMed:32027733};
CC -!- SUBUNIT: Interacts with phosphorylated BCL2L11 isoform BIMEL; this
CC interaction leads to BCL2L11 deubiquitination and stabilization.
CC {ECO:0000250|UniProtKB:Q8CEG8}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol
CC {ECO:0000250|UniProtKB:Q8CEG8}. Nucleus {ECO:0000250|UniProtKB:Q8CEG8}.
CC -!- DISEASE: Intellectual developmental disorder, X-linked 105 (XLID105)
CC [MIM:300984]: A form of intellectual disability, a disorder
CC characterized by significantly below average general intellectual
CC functioning associated with impairments in adaptive behavior and
CC manifested during the developmental period. Intellectual deficiency is
CC the only primary symptom of non-syndromic X-linked forms, while
CC syndromic forms present with associated physical, neurological and/or
CC psychiatric manifestations. {ECO:0000269|PubMed:25644381}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the peptidase C19 family. {ECO:0000305}.
CC -!- CAUTION: Although strongly related to USP22, which deubiquitinates
CC histones, lacks the N-terminal UBP-type zinc finger, suggesting it does
CC not have the ability to deubiquitinate histones. {ECO:0000305}.
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DR EMBL; AF238380; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; DR004246; -; NOT_ANNOTATED_CDS; mRNA.
DR CCDS; CCDS65260.1; -.
DR RefSeq; NP_001138545.1; NM_001145073.2.
DR AlphaFoldDB; A6NNY8; -.
DR SMR; A6NNY8; -.
DR BioGRID; 133302; 29.
DR IntAct; A6NNY8; 6.
DR MINT; A6NNY8; -.
DR STRING; 9606.ENSP00000483631; -.
DR BindingDB; A6NNY8; -.
DR ChEMBL; CHEMBL4630801; -.
DR MEROPS; C19.106; -.
DR iPTMnet; A6NNY8; -.
DR PhosphoSitePlus; A6NNY8; -.
DR BioMuta; USP27X; -.
DR EPD; A6NNY8; -.
DR jPOST; A6NNY8; -.
DR MassIVE; A6NNY8; -.
DR MaxQB; A6NNY8; -.
DR PeptideAtlas; A6NNY8; -.
DR PRIDE; A6NNY8; -.
DR ProteomicsDB; 1647; -.
DR Antibodypedia; 73225; 69 antibodies from 14 providers.
DR DNASU; 389856; -.
DR Ensembl; ENST00000621775.2; ENSP00000483631.1; ENSG00000273820.2.
DR GeneID; 389856; -.
DR KEGG; hsa:389856; -.
DR MANE-Select; ENST00000621775.2; ENSP00000483631.1; NM_001145073.3; NP_001138545.1.
DR UCSC; uc033edm.2; human.
DR CTD; 389856; -.
DR DisGeNET; 389856; -.
DR GeneCards; USP27X; -.
DR HGNC; HGNC:13486; USP27X.
DR HPA; ENSG00000273820; Low tissue specificity.
DR MalaCards; USP27X; -.
DR MIM; 300975; gene.
DR MIM; 300984; phenotype.
DR neXtProt; NX_A6NNY8; -.
DR OpenTargets; ENSG00000273820; -.
DR Orphanet; 777; X-linked non-syndromic intellectual disability.
DR PharmGKB; PA134993614; -.
DR VEuPathDB; HostDB:ENSG00000273820; -.
DR eggNOG; KOG1867; Eukaryota.
DR GeneTree; ENSGT00940000162674; -.
DR HOGENOM; CLU_008279_11_0_1; -.
DR InParanoid; A6NNY8; -.
DR OMA; QCSMPGL; -.
DR OrthoDB; 929408at2759; -.
DR PhylomeDB; A6NNY8; -.
DR PathwayCommons; A6NNY8; -.
DR SignaLink; A6NNY8; -.
DR BioGRID-ORCS; 389856; 10 hits in 678 CRISPR screens.
DR GenomeRNAi; 389856; -.
DR Pharos; A6NNY8; Tbio.
DR PRO; PR:A6NNY8; -.
DR Proteomes; UP000005640; Chromosome X.
DR RNAct; A6NNY8; protein.
DR Bgee; ENSG00000273820; Expressed in buccal mucosa cell and 169 other tissues.
DR Genevisible; A6NNY8; HS.
DR GO; GO:0005829; C:cytosol; IEA:UniProtKB-SubCell.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0004843; F:cysteine-type deubiquitinase activity; ISS:UniProtKB.
DR GO; GO:0004197; F:cysteine-type endopeptidase activity; IDA:UniProtKB.
DR GO; GO:1990380; F:Lys48-specific deubiquitinase activity; ISS:UniProtKB.
DR GO; GO:0061578; F:Lys63-specific deubiquitinase activity; ISS:UniProtKB.
DR GO; GO:0051607; P:defense response to virus; IMP:UniProtKB.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:0043065; P:positive regulation of apoptotic process; ISS:UniProtKB.
DR GO; GO:0060340; P:positive regulation of type I interferon-mediated signaling pathway; IDA:UniProtKB.
DR GO; GO:0016579; P:protein deubiquitination; ISS:UniProtKB.
DR GO; GO:0071108; P:protein K48-linked deubiquitination; IDA:UniProtKB.
DR GO; GO:0070536; P:protein K63-linked deubiquitination; ISS:UniProtKB.
DR GO; GO:0050821; P:protein stabilization; IDA:UniProtKB.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IEA:InterPro.
DR InterPro; IPR038765; Papain-like_cys_pep_sf.
DR InterPro; IPR001394; Peptidase_C19_UCH.
DR InterPro; IPR018200; USP_CS.
DR InterPro; IPR028889; USP_dom.
DR Pfam; PF00443; UCH; 1.
DR SUPFAM; SSF54001; SSF54001; 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 Cytoplasm; Disease variant; Hydrolase; Immunity; Innate immunity;
KW Intellectual disability; Nucleus; Protease; Reference proteome;
KW Thiol protease; Ubl conjugation pathway.
FT CHAIN 1..438
FT /note="Ubiquitin carboxyl-terminal hydrolase 27"
FT /id="PRO_0000306334"
FT DOMAIN 78..421
FT /note="USP"
FT ACT_SITE 87
FT /note="Nucleophile"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10092,
FT ECO:0000255|PROSITE-ProRule:PRU10093,
FT ECO:0000305|PubMed:31534008, ECO:0000305|PubMed:32027733"
FT ACT_SITE 380
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10092,
FT ECO:0000255|PROSITE-ProRule:PRU10093,
FT ECO:0000305|PubMed:32027733"
FT VARIANT 381
FT /note="Y -> H (in XLID105; dbSNP:rs886038211)"
FT /evidence="ECO:0000269|PubMed:25644381"
FT /id="VAR_077830"
FT MUTAGEN 87
FT /note="C->A: Abolished deubiquitinase activity; impaired
FT ability to mediate deubiquitination of CGAS."
FT /evidence="ECO:0000269|PubMed:31534008"
FT MUTAGEN 87
FT /note="C->S: Abolished deubiquitinase activity; impaired
FT ability to mediate deubiquitination of DDX58; when
FT associated with A-380."
FT /evidence="ECO:0000269|PubMed:32027733"
FT MUTAGEN 380
FT /note="H->A: Abolished deubiquitinase activity; impaired
FT ability to mediate deubiquitination of DDX58; when
FT associated with S-87."
FT /evidence="ECO:0000269|PubMed:32027733"
FT CONFLICT 32
FT /note="E -> D (in Ref. 2; DR004246)"
FT /evidence="ECO:0000305"
FT CONFLICT 45
FT /note="E -> D (in Ref. 2; DR004246)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 438 AA; 49630 MW; B6BFD18C62B3774C CRC64;
MCKDYVYDKD IEQIAKEEQG EALKLQASTS TEVSHQQCSV PGLGEKFPTW ETTKPELELL
GHNPRRRRIT SSFTIGLRGL INLGNTCFMN CIVQALTHTP ILRDFFLSDR HRCEMPSPEL
CLVCEMSSLF RELYSGNPSP HVPYKLLHLV WIHARHLAGY RQQDAHEFLI AALDVLHRHC
KGDDVGKAAN NPNHCNCIID QIFTGGLQSD VTCQACHGVS TTIDPCWDIS LDLPGSCTSF
WPMSPGRESS VNGESHIPGI TTLTDCLRRF TRPEHLGSSA KIKCGSCQSY QESTKQLTMN
KLPVVACFHF KRFEHSAKQR RKITTYISFP LELDMTPFMA SSKESRMNGQ LQLPTNSGNN
ENKYSLFAVV NHQGTLESGH YTSFIRHHKD QWFKCDDAVI TKASIKDVLD SEGYLLFYHK
QVLEHESEKV KEMNTQAY
