UBP18_HUMAN
ID UBP18_HUMAN Reviewed; 372 AA.
AC Q9UMW8; Q53Y90; Q6IAD9; Q9NY71;
DT 01-DEC-2000, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-2000, sequence version 1.
DT 03-AUG-2022, entry version 187.
DE RecName: Full=Ubl carboxyl-terminal hydrolase 18;
DE EC=3.4.19.-;
DE AltName: Full=43 kDa ISG15-specific protease;
DE Short=hUBP43;
DE AltName: Full=ISG15-specific-processing protease;
DE AltName: Full=Ubl thioesterase 18;
GN Name=USP18; Synonyms=ISG43;
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] (ISOFORM 1).
RA Li X.-L., Blackford J.A., Judge C.S., Liu M., Xiao W., Kalvakolanu D.V.,
RA Hassel B.A.;
RT "RNase-L-dependent regulation of a novel interferon-stimulated gene:
RT feedback inhibition of the interferon response.";
RL Submitted (AUG-1999) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=10777664; DOI=10.1006/geno.2000.6148;
RA Schwer H., Liu L.Q., Zhou L., Little M.T., Pan Z., Hetherington C.J.;
RT "Cloning and characterization of a novel human ubiquitin-specific protease,
RT a homologue of murine UBP43 (Usp18).";
RL Genomics 65:44-52(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain;
RX PubMed=11230166; DOI=10.1101/gr.gr1547r;
RA Wiemann S., Weil B., Wellenreuther R., Gassenhuber J., Glassl S.,
RA Ansorge W., Boecher M., Bloecker H., Bauersachs S., Blum H., Lauber J.,
RA Duesterhoeft A., Beyer A., Koehrer K., Strack N., Mewes H.-W.,
RA Ottenwaelder B., Obermaier B., Tampe J., Heubner D., Wambutt R., Korn B.,
RA Klein M., Poustka A.;
RT "Towards a catalog of human genes and proteins: sequencing and analysis of
RT 500 novel complete protein coding human cDNAs.";
RL Genome Res. 11:422-435(2001).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RX PubMed=15461802; DOI=10.1186/gb-2004-5-10-r84;
RA Collins J.E., Wright C.L., Edwards C.A., Davis M.P., Grinham J.A.,
RA Cole C.G., Goward M.E., Aguado B., Mallya M., Mokrab Y., Huckle E.J.,
RA Beare D.M., Dunham I.;
RT "A genome annotation-driven approach to cloning the human ORFeome.";
RL Genome Biol. 5:R84.1-R84.11(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Ovary;
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 NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT MET-169.
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Uterus;
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 [9]
RP FUNCTION.
RX PubMed=11788588; DOI=10.1074/jbc.m109078200;
RA Malakhov M.P., Malakhova O.A., Kim K.I., Ritchie K.J., Zhang D.-E.;
RT "UBP43 (USP18) specifically removes ISG15 from conjugated proteins.";
RL J. Biol. Chem. 277:9976-9981(2002).
RN [10]
RP ALTERNATIVE INITIATION (ISOFORM 2), CTG START CODON (ISOFORM 2), FUNCTION
RP (ISOFORM 2), AND SUBCELLULAR LOCATION.
RX PubMed=22170061; DOI=10.1074/jbc.m111.255570;
RA Burkart C., Fan J.B., Zhang D.E.;
RT "Two independent mechanisms promote expression of an N-terminal truncated
RT USP18 isoform with higher DeISGylation activity in the nucleus.";
RL J. Biol. Chem. 287:4883-4893(2012).
RN [11]
RP FUNCTION, INVOLVEMENT IN PTORCH2, AND VARIANT PTORCH2 218-GLN--CYS-372 DEL.
RX PubMed=27325888; DOI=10.1084/jem.20151529;
RA Meuwissen M.E., Schot R., Buta S., Oudesluijs G., Tinschert S., Speer S.D.,
RA Li Z., van Unen L., Heijsman D., Goldmann T., Lequin M.H., Kros J.M.,
RA Stam W., Hermann M., Willemsen R., Brouwer R.W., Van Ijcken W.F.,
RA Martin-Fernandez M., de Coo I., Dudink J., de Vries F.A.,
RA Bertoli Avella A., Prinz M., Crow Y.J., Verheijen F.W., Pellegrini S.,
RA Bogunovic D., Mancini G.M.;
RT "Human USP18 deficiency underlies type 1 interferonopathy leading to severe
RT pseudo-TORCH syndrome.";
RL J. Exp. Med. 213:1163-1174(2016).
RN [12]
RP FUNCTION, INTERACTION WITH IFNAR2 AND STAT2, AND REGION.
RX PubMed=28165510; DOI=10.1038/nsmb.3378;
RA Arimoto K.I., Loechte S., Stoner S.A., Burkart C., Zhang Y., Miyauchi S.,
RA Wilmes S., Fan J.B., Heinisch J.J., Li Z., Yan M., Pellegrini S.,
RA Colland F., Piehler J., Zhang D.E.;
RT "STAT2 is an essential adaptor in USP18-mediated suppression of type I
RT interferon signaling.";
RL Nat. Struct. Mol. Biol. 24:279-289(2017).
RN [13]
RP INTERACTION WITH STAT2.
RX PubMed=31836668; DOI=10.1126/sciimmunol.aav7501;
RA Duncan C.J.A., Thompson B.J., Chen R., Rice G.I., Gothe F., Young D.F.,
RA Lovell S.C., Shuttleworth V.G., Brocklebank V., Corner B., Skelton A.J.,
RA Bondet V., Coxhead J., Duffy D., Fourrage C., Livingston J.H., Pavaine J.,
RA Cheesman E., Bitetti S., Grainger A., Acres M., Innes B.A., Mikulasova A.,
RA Sun R., Hussain R., Wright R., Wynn R., Zarhrate M., Zeef L.A.H., Wood K.,
RA Hughes S.M., Harris C.L., Engelhardt K.R., Crow Y.J., Randall R.E.,
RA Kavanagh D., Hambleton S., Briggs T.A.;
RT "Severe type I interferonopathy and unrestrained interferon signaling due
RT to a homozygous germline mutation in STAT2.";
RL Sci. Immunol. 4:0-0(2019).
RN [14]
RP INTERACTION WITH STAT2.
RX PubMed=32092142; DOI=10.1084/jem.20192319;
RA Gruber C., Martin-Fernandez M., Ailal F., Qiu X., Taft J., Altman J.,
RA Rosain J., Buta S., Bousfiha A., Casanova J.L., Bustamante J.,
RA Bogunovic D.;
RT "Homozygous STAT2 gain-of-function mutation by loss of USP18 activity in a
RT patient with type I interferonopathy.";
RL J. Exp. Med. 217:0-0(2020).
CC -!- FUNCTION: Involved in the negative regulation of the inflammatory
CC response triggered by type I interferon (PubMed:28165510,
CC PubMed:27325888). Upon recruitment by STAT2 to the type I IFN receptor
CC subunit IFNAR2 interferes with the assembly of the ternary interferon-
CC IFNAR1-IFNAR2 complex and acts as a negative regulator of the type I
CC IFN signaling pathway (PubMed:28165510). Also regulates protein
CC ISGylation. Can efficiently cleave only ISG15 fusions including native
CC ISG15 conjugates linked via isopeptide bonds. Necessary to maintain a
CC critical cellular balance of ISG15-conjugated proteins in both healthy
CC and stressed organisms (PubMed:11788588). {ECO:0000269|PubMed:11788588,
CC ECO:0000269|PubMed:27325888, ECO:0000269|PubMed:28165510}.
CC -!- FUNCTION: [Isoform 2]: Has enzymatic activity similar to isoform 1 and
CC interferes with type I interferon signaling. Major deISGylation enzyme
CC for nuclear proteins (PubMed:22170061). {ECO:0000269|PubMed:22170061}.
CC -!- SUBUNIT: Interacts with STAT2; the interaction is direct
CC (PubMed:28165510, PubMed:31836668, PubMed:32092142). Interacts with
CC IFNAR2; indirectly via STAT2, it negatively regulates the assembly of
CC the ternary interferon-IFNAR1-IFNAR2 complex and inhibits type I
CC interferon signaling (PubMed:28165510). {ECO:0000269|PubMed:28165510,
CC ECO:0000269|PubMed:31836668, ECO:0000269|PubMed:32092142}.
CC -!- INTERACTION:
CC Q9UMW8; P42858: HTT; NbExp=3; IntAct=EBI-356206, EBI-466029;
CC Q9UMW8; P48551: IFNAR2; NbExp=4; IntAct=EBI-356206, EBI-958408;
CC Q9UMW8; P05161: ISG15; NbExp=9; IntAct=EBI-356206, EBI-746466;
CC Q9UMW8; Q3LFD5: USP41; NbExp=2; IntAct=EBI-356206, EBI-2511843;
CC -!- SUBCELLULAR LOCATION: [Isoform 1]: Cytoplasm
CC {ECO:0000269|PubMed:22170061}.
CC -!- SUBCELLULAR LOCATION: [Isoform 2]: Nucleus
CC {ECO:0000269|PubMed:22170061}. Cytoplasm {ECO:0000269|PubMed:22170061}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative initiation; Named isoforms=2;
CC Name=1;
CC IsoId=Q9UMW8-1; Sequence=Displayed;
CC Name=2; Synonyms=USP18-sf;
CC IsoId=Q9UMW8-2; Sequence=VSP_055236;
CC -!- DISEASE: Pseudo-TORCH syndrome 2 (PTORCH2) [MIM:617397]: An autosomal
CC recessive multisystem disorder characterized by antenatal onset of
CC intracranial hemorrhage, calcification, brain malformations, liver
CC dysfunction, and often thrombocytopenia. Affected individuals tend to
CC have respiratory insufficiency and seizures, and die in infancy. The
CC phenotype resembles the sequelae of intrauterine infection, but there
CC is no evidence of an infectious agent. {ECO:0000269|PubMed:27325888}.
CC Note=The disease is caused by variants affecting the gene represented
CC in this entry.
CC -!- MISCELLANEOUS: [Isoform 2]: Produced by alternative initiation at a CTG
CC start codon. An IRES Element in the 5' region contributes to
CC expression. {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the peptidase C19 family. {ECO:0000305}.
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DR EMBL; AF176642; AAD49967.1; -; mRNA.
DR EMBL; AJ243526; CAB76398.1; -; mRNA.
DR EMBL; AL136690; CAB66625.1; -; mRNA.
DR EMBL; BT006835; AAP35481.1; -; mRNA.
DR EMBL; CT841507; CAJ86437.1; -; mRNA.
DR EMBL; AK313385; BAG36183.1; -; mRNA.
DR EMBL; CR457216; CAG33497.1; -; mRNA.
DR EMBL; BC014896; AAH14896.1; -; mRNA.
DR CCDS; CCDS13752.1; -. [Q9UMW8-1]
DR RefSeq; NP_059110.2; NM_017414.3. [Q9UMW8-1]
DR AlphaFoldDB; Q9UMW8; -.
DR SMR; Q9UMW8; -.
DR BioGRID; 116430; 49.
DR DIP; DIP-42723N; -.
DR IntAct; Q9UMW8; 23.
DR MINT; Q9UMW8; -.
DR STRING; 9606.ENSP00000215794; -.
DR BindingDB; Q9UMW8; -.
DR ChEMBL; CHEMBL3407317; -.
DR MEROPS; C19.030; -.
DR iPTMnet; Q9UMW8; -.
DR PhosphoSitePlus; Q9UMW8; -.
DR BioMuta; USP18; -.
DR DMDM; 10720335; -.
DR jPOST; Q9UMW8; -.
DR MassIVE; Q9UMW8; -.
DR MaxQB; Q9UMW8; -.
DR PaxDb; Q9UMW8; -.
DR PeptideAtlas; Q9UMW8; -.
DR PRIDE; Q9UMW8; -.
DR ProteomicsDB; 85214; -. [Q9UMW8-1]
DR Antibodypedia; 22768; 127 antibodies from 31 providers.
DR DNASU; 11274; -.
DR Ensembl; ENST00000215794.8; ENSP00000215794.7; ENSG00000184979.10. [Q9UMW8-1]
DR GeneID; 11274; -.
DR KEGG; hsa:11274; -.
DR MANE-Select; ENST00000215794.8; ENSP00000215794.7; NM_017414.4; NP_059110.2.
DR UCSC; uc002zny.4; human. [Q9UMW8-1]
DR CTD; 11274; -.
DR DisGeNET; 11274; -.
DR GeneCards; USP18; -.
DR HGNC; HGNC:12616; USP18.
DR HPA; ENSG00000184979; Low tissue specificity.
DR MalaCards; USP18; -.
DR MIM; 607057; gene.
DR MIM; 617397; phenotype.
DR neXtProt; NX_Q9UMW8; -.
DR OpenTargets; ENSG00000184979; -.
DR Orphanet; 481665; USP18 deficiency.
DR PharmGKB; PA37242; -.
DR VEuPathDB; HostDB:ENSG00000184979; -.
DR eggNOG; KOG1863; Eukaryota.
DR GeneTree; ENSGT00940000161720; -.
DR HOGENOM; CLU_062837_0_0_1; -.
DR InParanoid; Q9UMW8; -.
DR OMA; AYCLQKC; -.
DR OrthoDB; 147564at2759; -.
DR PhylomeDB; Q9UMW8; -.
DR PathwayCommons; Q9UMW8; -.
DR Reactome; R-HSA-1169408; ISG15 antiviral mechanism.
DR Reactome; R-HSA-5689880; Ub-specific processing proteases.
DR Reactome; R-HSA-912694; Regulation of IFNA/IFNB signaling.
DR SignaLink; Q9UMW8; -.
DR BioGRID-ORCS; 11274; 90 hits in 1114 CRISPR screens.
DR GeneWiki; USP18; -.
DR GenomeRNAi; 11274; -.
DR Pharos; Q9UMW8; Tbio.
DR PRO; PR:Q9UMW8; -.
DR Proteomes; UP000005640; Chromosome 22.
DR RNAct; Q9UMW8; protein.
DR Bgee; ENSG00000184979; Expressed in left testis and 104 other tissues.
DR Genevisible; Q9UMW8; HS.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IDA:LIFEdb.
DR GO; GO:0004843; F:cysteine-type deubiquitinase activity; IBA:GO_Central.
DR GO; GO:0004197; F:cysteine-type endopeptidase activity; IBA:GO_Central.
DR GO; GO:0019785; F:ISG15-specific peptidase activity; EXP:Reactome.
DR GO; GO:0060339; P:negative regulation of type I interferon-mediated signaling pathway; IDA:UniProtKB.
DR GO; GO:0016579; P:protein deubiquitination; IBA:GO_Central.
DR GO; GO:0050727; P:regulation of inflammatory response; IMP:UniProtKB.
DR GO; GO:0009617; P:response to bacterium; IEA:Ensembl.
DR GO; GO:0035634; P:response to stilbenoid; IEA:Ensembl.
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 Alternative initiation; Cytoplasm; Hydrolase; Nucleus; Protease;
KW Reference proteome; Thiol protease; Ubl conjugation pathway.
FT CHAIN 1..372
FT /note="Ubl carboxyl-terminal hydrolase 18"
FT /id="PRO_0000080644"
FT DOMAIN 55..370
FT /note="USP"
FT /evidence="ECO:0000255"
FT REGION 19..45
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 36..51
FT /note="Mediates interaction with IFNAR2"
FT /evidence="ECO:0000269|PubMed:28165510"
FT REGION 51..112
FT /note="Mediates interaction with STAT2"
FT /evidence="ECO:0000269|PubMed:28165510"
FT REGION 303..312
FT /note="Mediates interaction with STAT2 and necessary for
FT the negative regulation of the type I IFN signaling
FT pathway"
FT /evidence="ECO:0000269|PubMed:28165510"
FT REGION 313..372
FT /note="Mediates interaction with IFNAR2"
FT /evidence="ECO:0000269|PubMed:28165510"
FT COMPBIAS 23..45
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 64
FT /note="Nucleophile"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10092,
FT ECO:0000255|PROSITE-ProRule:PRU10093"
FT ACT_SITE 318
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10092,
FT ECO:0000255|PROSITE-ProRule:PRU10093"
FT VAR_SEQ 1..16
FT /note="MSKAFGLLRQICQSIL -> M (in isoform 2)"
FT /evidence="ECO:0000305"
FT /id="VSP_055236"
FT VARIANT 169
FT /note="T -> M (in dbSNP:rs3180408)"
FT /evidence="ECO:0000269|Ref.7"
FT /id="VAR_024589"
FT VARIANT 218..372
FT /note="Missing (in PTORCH2)"
FT /evidence="ECO:0000269|PubMed:27325888"
FT /id="VAR_078772"
FT CONFLICT 332
FT /note="F -> S (in Ref. 2; CAB76398)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 372 AA; 43011 MW; 60248E8D4CC42BF0 CRC64;
MSKAFGLLRQ ICQSILAESS QSPADLEEKK EEDSNMKREQ PRERPRAWDY PHGLVGLHNI
GQTCCLNSLI QVFVMNVDFT RILKRITVPR GADEQRRSVP FQMLLLLEKM QDSRQKAVRP
LELAYCLQKC NVPLFVQHDA AQLYLKLWNL IKDQITDVHL VERLQALYTI RVKDSLICVD
CAMESSRNSS MLTLPLSLFD VDSKPLKTLE DALHCFFQPR ELSSKSKCFC ENCGKKTRGK
QVLKLTHLPQ TLTIHLMRFS IRNSQTRKIC HSLYFPQSLD FSQILPMKRE SCDAEEQSGG
QYELFAVIAH VGMADSGHYC VYIRNAVDGK WFCFNDSNIC LVSWEDIQCT YGNPNYHWQE
TAYLLVYMKM EC
