U17L2_HUMAN
ID U17L2_HUMAN Reviewed; 530 AA.
AC Q6R6M4;
DT 29-APR-2008, integrated into UniProtKB/Swiss-Prot.
DT 29-APR-2008, sequence version 2.
DT 03-AUG-2022, entry version 133.
DE RecName: Full=Ubiquitin carboxyl-terminal hydrolase 17;
DE Short=USP17;
DE EC=3.4.19.12 {ECO:0000269|PubMed:14699124, ECO:0000269|PubMed:20228808, ECO:0000269|PubMed:20368735};
DE AltName: Full=Deubiquitinating enzyme 17-like protein 2;
DE AltName: Full=Deubiquitinating protein 3;
DE Short=DUB-3;
DE AltName: Full=Ubiquitin carboxyl-terminal hydrolase 17-like protein 2;
DE AltName: Full=Ubiquitin thioesterase 17-like protein 2;
DE AltName: Full=Ubiquitin-specific-processing protease 17-like protein 2;
GN Name=USP17L2;
GN Synonyms=DUB3, USP17, USP17H, USP17I, USP17J, USP17K, USP17L, USP17M;
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], FUNCTION, CATALYTIC ACTIVITY, INDUCTION BY
RP CYTOKINES, TISSUE SPECIFICITY, AND MUTAGENESIS OF CYS-89.
RX PubMed=14699124; DOI=10.1074/jbc.m311291200;
RA Burrows J.F., McGrattan M.J., Rascle A., Humbert M., Baek K.-H.,
RA Johnston J.A.;
RT "DUB-3, a cytokine-inducible deubiquitinating enzyme that blocks
RT proliferation.";
RL J. Biol. Chem. 279:13993-14000(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16421571; DOI=10.1038/nature04406;
RA Nusbaum C., Mikkelsen T.S., Zody M.C., Asakawa S., Taudien S., Garber M.,
RA Kodira C.D., Schueler M.G., Shimizu A., Whittaker C.A., Chang J.L.,
RA Cuomo C.A., Dewar K., FitzGerald M.G., Yang X., Allen N.R., Anderson S.,
RA Asakawa T., Blechschmidt K., Bloom T., Borowsky M.L., Butler J., Cook A.,
RA Corum B., DeArellano K., DeCaprio D., Dooley K.T., Dorris L. III,
RA Engels R., Gloeckner G., Hafez N., Hagopian D.S., Hall J.L., Ishikawa S.K.,
RA Jaffe D.B., Kamat A., Kudoh J., Lehmann R., Lokitsang T., Macdonald P.,
RA Major J.E., Matthews C.D., Mauceli E., Menzel U., Mihalev A.H.,
RA Minoshima S., Murayama Y., Naylor J.W., Nicol R., Nguyen C., O'Leary S.B.,
RA O'Neill K., Parker S.C.J., Polley A., Raymond C.K., Reichwald K.,
RA Rodriguez J., Sasaki T., Schilhabel M., Siddiqui R., Smith C.L.,
RA Sneddon T.P., Talamas J.A., Tenzin P., Topham K., Venkataraman V., Wen G.,
RA Yamazaki S., Young S.K., Zeng Q., Zimmer A.R., Rosenthal A., Birren B.W.,
RA Platzer M., Shimizu N., Lander E.S.;
RT "DNA sequence and analysis of human chromosome 8.";
RL Nature 439:331-335(2006).
RN [3]
RP NOMENCLATURE.
RX PubMed=15780755; DOI=10.1016/j.ygeno.2004.11.013;
RA Burrows J.F., McGrattan M.J., Johnston J.A.;
RT "The DUB/USP17 deubiquitinating enzymes, a multigene family within a
RT tandemly repeated sequence.";
RL Genomics 85:524-529(2005).
RN [4]
RP NOMENCLATURE, AND FUNCTION IN APOPTOSIS.
RX PubMed=17109758; DOI=10.1186/1471-2164-7-292;
RA Shin J.-M., Yoo K.-J., Kim M.-S., Kim D., Baek K.-H.;
RT "Hyaluronan- and RNA-binding deubiquitinating enzymes of USP17 family
RT members associated with cell viability.";
RL BMC Genomics 7:292-292(2006).
RN [5]
RP FUNCTION IN CELL PROLIFERATION, AND SUBCELLULAR LOCATION.
RX PubMed=19188362; DOI=10.1074/jbc.m807216200;
RA Burrows J.F., Kelvin A.A., McFarlane C., Burden R.E., McGrattan M.J.,
RA De la Vega M., Govender U., Quinn D.J., Dib K., Gadina M., Scott C.J.,
RA Johnston J.A.;
RT "USP17 regulates Ras activation and cell proliferation by blocking RCE1
RT activity.";
RL J. Biol. Chem. 284:9587-9595(2009).
RN [6]
RP IDENTIFICATION.
RX PubMed=20403174; DOI=10.1186/1471-2164-11-250;
RA Burrows J.F., Scott C.J., Johnston J.A.;
RT "The DUB/USP17 deubiquitinating enzymes: a gene family within a tandemly
RT repeated sequence, is also embedded within the copy number variable beta-
RT defensin cluster.";
RL BMC Genomics 11:250-250(2010).
RN [7]
RP FUNCTION, AND INDUCTION.
RX PubMed=20388806; DOI=10.1158/0008-5472.can-09-4152;
RA McFarlane C., Kelvin A.A., de la Vega M., Govender U., Scott C.J.,
RA Burrows J.F., Johnston J.A.;
RT "The deubiquitinating enzyme USP17 is highly expressed in tumor biopsies,
RT is cell cycle regulated, and is required for G1-S progression.";
RL Cancer Res. 70:3329-3339(2010).
RN [8]
RP CATALYTIC ACTIVITY, AND FUNCTION IN CELLULAR ANTIVIRAL RESPONSE.
RX PubMed=20368735; DOI=10.1038/cr.2010.41;
RA Chen R., Zhang L., Zhong B., Tan B., Liu Y., Shu H.B.;
RT "The ubiquitin-specific protease 17 is involved in virus-triggered type I
RT IFN signaling.";
RL Cell Res. 20:802-811(2010).
RN [9]
RP FUNCTION.
RX PubMed=20147298; DOI=10.1074/jbc.m109.081448;
RA de la Vega M., Burrows J.F., McFarlane C., Govender U., Scott C.J.,
RA Johnston J.A.;
RT "The deubiquitinating enzyme USP17 blocks N-Ras membrane trafficking and
RT activation but leaves K-Ras unaffected.";
RL J. Biol. Chem. 285:12028-12036(2010).
RN [10]
RP CATALYTIC ACTIVITY, AND FUNCTION IN CELL PROLIFERATION.
RX PubMed=20228808; DOI=10.1038/ncb2041;
RA Pereg Y., Liu B.Y., O'Rourke K.M., Sagolla M., Dey A., Komuves L.,
RA French D.M., Dixit V.M.;
RT "Ubiquitin hydrolase Dub3 promotes oncogenic transformation by stabilizing
RT Cdc25A.";
RL Nat. Cell Biol. 12:400-406(2010).
RN [11]
RP FUNCTION, INTERACTION WITH SUDS3, AND SUBCELLULAR LOCATION.
RX PubMed=21239494; DOI=10.1074/jbc.m110.162321;
RA Ramakrishna S., Suresh B., Lee E.J., Lee H.J., Ahn W.S., Baek K.H.;
RT "Lys-63-specific deubiquitination of SDS3 by USP17 regulates HDAC
RT activity.";
RL J. Biol. Chem. 286:10505-10514(2011).
RN [12]
RP FUNCTION IN CELL MIGRATION, AND INDUCTION BY CHEMOKINE.
RX PubMed=21448158; DOI=10.1038/ncomms1243;
RA de la Vega M., Kelvin A.A., Dunican D.J., McFarlane C., Burrows J.F.,
RA Jaworski J., Stevenson N.J., Dib K., Rappoport J.Z., Scott C.J., Long A.,
RA Johnston J.A.;
RT "The deubiquitinating enzyme USP17 is essential for GTPase subcellular
RT localization and cell motility.";
RL Nat. Commun. 2:259-259(2011).
CC -!- FUNCTION: Deubiquitinating enzyme that removes conjugated ubiquitin
CC from specific proteins to regulate different cellular processes.
CC Regulates cell proliferation by deubiquitinating and inhibiting RCE1
CC thereby controlling the small GTPases NRAS and HRAS localization and
CC activation. In parallel, mediates deubiquitination of CDC25A,
CC preventing CDC25A degradation by the proteasome during the G1/S and
CC G2/M phases promoting cell-cycle progression. Also regulates cell
CC proliferation and apoptosis through deubiquitination of SUDS3 a
CC regulator of histone deacetylation. Through activation of the Rho
CC family GTPases RAC1A, CDC42 and RHOA, regulates cell migration. Through
CC the cleavage of 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains of
CC the cytoplasmic innate immune receptors DDX58 and IFIH1 stimulates the
CC cellular response to viral infection. {ECO:0000269|PubMed:14699124,
CC ECO:0000269|PubMed:17109758, ECO:0000269|PubMed:19188362,
CC ECO:0000269|PubMed:20147298, ECO:0000269|PubMed:20228808,
CC ECO:0000269|PubMed:20368735, ECO:0000269|PubMed:20388806,
CC ECO:0000269|PubMed:21239494, ECO:0000269|PubMed:21448158}.
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:14699124,
CC ECO:0000269|PubMed:20228808, ECO:0000269|PubMed:20368735};
CC -!- SUBUNIT: Interacts with SUDS3; the interaction is direct.
CC {ECO:0000269|PubMed:21239494}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:21239494}.
CC Endoplasmic reticulum {ECO:0000269|PubMed:19188362}.
CC -!- TISSUE SPECIFICITY: Broadly expressed. {ECO:0000269|PubMed:14699124}.
CC -!- INDUCTION: Up-regulated by IL4/interleukin-4, IL6/interleukin-6 and
CC chemokines including CXCL8 and CXCL12 (at protein level). Up-regulated
CC during the G1/S transition of the cell cycle.
CC {ECO:0000269|PubMed:14699124, ECO:0000269|PubMed:20388806,
CC ECO:0000269|PubMed:21448158}.
CC -!- MISCELLANEOUS: Overexpressed in a subset of human breast cancers,
CC overexpression leading to an abnormally high level of CDC25A, which
CC arrests cells through replication stress or premature mitosis, the
CC latter occurring when CDK1 is activated inappropriately.
CC {ECO:0000305|PubMed:20228808}.
CC -!- SIMILARITY: Belongs to the peptidase C19 family. USP17 subfamily.
CC {ECO:0000305}.
CC -!- CAUTION: The RS447 megasatellite DNA is a highly polymorphic conserved
CC tandem repetitive sequence which contains a copy of the USP17 gene. It
CC is present with an interindividual variation in copy number, ranging
CC from 20 to 103, and can be found in the genome both on chromosome 4 and
CC chromosome 8. USP17 is also frequently named DUB3 in the literature.
CC The high similarity between the UPS17-like genes makes impossible to
CC clearly assign data to one of the genes of the family. Oligonucleotides
CC designed in RNAi experiments are for instance not specific of a given
CC UPS17-like gene. {ECO:0000305}.
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DR EMBL; AY509884; AAR91701.1; -; mRNA.
DR EMBL; AC130366; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR CCDS; CCDS43713.1; -.
DR RefSeq; NP_958804.2; NM_201402.2.
DR AlphaFoldDB; Q6R6M4; -.
DR SMR; Q6R6M4; -.
DR BioGRID; 132019; 28.
DR IntAct; Q6R6M4; 4.
DR STRING; 9606.ENSP00000333329; -.
DR BindingDB; Q6R6M4; -.
DR ChEMBL; CHEMBL3739248; -.
DR MEROPS; C19.023; -.
DR MEROPS; C19.A83; -.
DR iPTMnet; Q6R6M4; -.
DR PhosphoSitePlus; Q6R6M4; -.
DR BioMuta; USP17L2; -.
DR DMDM; 187663988; -.
DR PaxDb; Q6R6M4; -.
DR PeptideAtlas; Q6R6M4; -.
DR PRIDE; Q6R6M4; -.
DR Antibodypedia; 22144; 120 antibodies from 20 providers.
DR DNASU; 377630; -.
DR Ensembl; ENST00000333796.4; ENSP00000333329.3; ENSG00000223443.3.
DR GeneID; 377630; -.
DR KEGG; hsa:377630; -.
DR MANE-Select; ENST00000333796.4; ENSP00000333329.3; NM_201402.3; NP_958804.2.
DR UCSC; uc003wvc.2; human.
DR CTD; 377630; -.
DR DisGeNET; 377630; -.
DR GeneCards; USP17L2; -.
DR HGNC; HGNC:34434; USP17L2.
DR HPA; ENSG00000223443; Tissue enriched (brain).
DR MIM; 610186; gene.
DR neXtProt; NX_Q6R6M4; -.
DR OpenTargets; ENSG00000223443; -.
DR PharmGKB; PA165586023; -.
DR VEuPathDB; HostDB:ENSG00000223443; -.
DR eggNOG; KOG1865; Eukaryota.
DR GeneTree; ENSGT00940000161948; -.
DR HOGENOM; CLU_008279_10_0_1; -.
DR InParanoid; Q6R6M4; -.
DR OrthoDB; 561804at2759; -.
DR PhylomeDB; Q6R6M4; -.
DR TreeFam; TF315281; -.
DR PathwayCommons; Q6R6M4; -.
DR Reactome; R-HSA-5689880; Ub-specific processing proteases.
DR Reactome; R-HSA-9648002; RAS processing.
DR SABIO-RK; Q6R6M4; -.
DR SignaLink; Q6R6M4; -.
DR BioGRID-ORCS; 377630; 17 hits in 993 CRISPR screens.
DR GenomeRNAi; 377630; -.
DR Pharos; Q6R6M4; Tbio.
DR PRO; PR:Q6R6M4; -.
DR Proteomes; UP000005640; Chromosome 8.
DR RNAct; Q6R6M4; protein.
DR Bgee; ENSG00000223443; Expressed in corpus callosum and 31 other tissues.
DR GO; GO:0005829; C:cytosol; IBA:GO_Central.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0004843; F:cysteine-type deubiquitinase activity; IDA:UniProtKB.
DR GO; GO:0004197; F:cysteine-type endopeptidase activity; IBA:GO_Central.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0071586; P:CAAX-box protein processing; IMP:UniProtKB.
DR GO; GO:0007049; P:cell cycle; IEA:UniProtKB-KW.
DR GO; GO:0000165; P:MAPK cascade; TAS:Reactome.
DR GO; GO:0034260; P:negative regulation of GTPase activity; IDA:UniProtKB.
DR GO; GO:0031064; P:negative regulation of histone deacetylation; IMP:UniProtKB.
DR GO; GO:0010955; P:negative regulation of protein processing; IMP:UniProtKB.
DR GO; GO:0090315; P:negative regulation of protein targeting to membrane; IMP:UniProtKB.
DR GO; GO:0043547; P:positive regulation of GTPase activity; IMP:UniProtKB.
DR GO; GO:1900245; P:positive regulation of MDA-5 signaling pathway; IMP:UniProtKB.
DR GO; GO:1900246; P:positive regulation of RIG-I signaling pathway; IMP:UniProtKB.
DR GO; GO:0016579; P:protein deubiquitination; IDA:UniProtKB.
DR GO; GO:0071108; P:protein K48-linked deubiquitination; IMP:UniProtKB.
DR GO; GO:0070536; P:protein K63-linked deubiquitination; IDA:UniProtKB.
DR GO; GO:0042981; P:regulation of apoptotic process; IMP:UniProtKB.
DR GO; GO:0030334; P:regulation of cell migration; IMP:UniProtKB.
DR GO; GO:0042127; P:regulation of cell population proliferation; IMP:UniProtKB.
DR GO; GO:0050691; P:regulation of defense response to virus by host; IMP:UniProtKB.
DR GO; GO:0110030; P:regulation of G2/MI transition of meiotic cell cycle; IMP:UniProtKB.
DR GO; GO:1900027; P:regulation of ruffle assembly; IMP: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; PS00973; USP_2; 1.
DR PROSITE; PS50235; USP_3; 1.
PE 1: Evidence at protein level;
KW Apoptosis; Cell cycle; Endoplasmic reticulum; Hydrolase; Nucleus; Protease;
KW Reference proteome; Thiol protease; Ubl conjugation pathway.
FT CHAIN 1..530
FT /note="Ubiquitin carboxyl-terminal hydrolase 17"
FT /id="PRO_0000331644"
FT DOMAIN 80..375
FT /note="USP"
FT REGION 382..416
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 399..530
FT /note="Mediates interaction with SUDS3"
FT /evidence="ECO:0000269|PubMed:21239494"
FT REGION 490..530
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 490..512
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 89
FT /note="Nucleophile"
FT ACT_SITE 334
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10093"
FT VARIANT 438
FT /note="K -> R (in dbSNP:rs12543578)"
FT /id="VAR_059750"
FT MUTAGEN 89
FT /note="C->S: Abolishes both enzymatic activity and effects
FT on cell proliferation."
FT /evidence="ECO:0000269|PubMed:14699124"
FT CONFLICT 66
FT /note="K -> E (in Ref. 1; AAR91701)"
FT /evidence="ECO:0000305"
FT CONFLICT 214
FT /note="S -> P (in Ref. 1; AAR91701)"
FT /evidence="ECO:0000305"
FT CONFLICT 332
FT /note="D -> N (in Ref. 1; AAR91701)"
FT /evidence="ECO:0000305"
FT CONFLICT 353
FT /note="K -> E (in Ref. 1; AAR91701)"
FT /evidence="ECO:0000305"
FT CONFLICT 357
FT /note="C -> S (in Ref. 1; AAR91701)"
FT /evidence="ECO:0000305"
FT CONFLICT 423
FT /note="R -> H (in Ref. 1; AAR91701)"
FT /evidence="ECO:0000305"
FT CONFLICT 440
FT /note="P -> L (in Ref. 1; AAR91701)"
FT /evidence="ECO:0000305"
FT CONFLICT 462
FT /note="N -> D (in Ref. 1; AAR91701)"
FT /evidence="ECO:0000305"
FT CONFLICT 494
FT /note="R -> P (in Ref. 1; AAR91701)"
FT /evidence="ECO:0000305"
FT CONFLICT 496
FT /note="D -> H (in Ref. 1; AAR91701)"
FT /evidence="ECO:0000305"
FT CONFLICT 500
FT /note="V -> M (in Ref. 1; AAR91701)"
FT /evidence="ECO:0000305"
FT CONFLICT 509
FT /note="Q -> R (in Ref. 1; AAR91701)"
FT /evidence="ECO:0000305"
FT CONFLICT 512
FT /note="T -> A (in Ref. 1; AAR91701)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 530 AA; 59619 MW; B117BB171376B0E4 CRC64;
MEDDSLYLGG EWQFNHFSKL TSSRPDAAFA EIQRTSLPEK SPLSSEARVD LCDDLAPVAR
QLAPRKKLPL SSRRPAAVGA GLQNMGNTCY ENASLQCLTY TPPLANYMLS REHSQTCQRP
KCCMLCTMQA HITWALHSPG HVIQPSQALA AGFHRGKQED AHEFLMFTVD AMKKACLPGH
KQVDHHSKDT TLIHQIFGGC WRSQIKCLHC HGISDTFDPY LDIALDIQAA QSVKQALEQL
VKPEELNGEN AYHCGLCLQR APASKTLTLH TSAKVLILVL KRFSDVTGNK LAKNVQYPEC
LDMQPYMSQQ NTGPLVYVLY AVLVHAGWSC HDGHYFSYVK AQEGQWYKMD DAKVTACSIT
SVLSQQAYVL FYIQKSEWER HSESVSRGRE PRALGAEDTD RRATQGELKR DHPCLQAPEL
DERLVERATQ ESTLDHWKFP QEQNKTKPEF NVRKVEGTLP PNVLVIHQSK YKCGMKNHHP
EQQSSLLNLS STTRTDQESV NTGTLASLQG RTRRSKGKNK HSKRALLVCQ
