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Symbol USP18 contributors: mct/npt - updated : 31-01-2015
HGNC name ubiquitin specific peptidase 18
HGNC id 12616
Location 22q11.21      Physical location : 18.632.757 - 18.660.160
Synonym name
  • ubiquitin processing protease 43 Kda
  • interferon stimulated gene
  • ubiquitin specific protease 18
  • weakly similar to T05H10.1 [C.elegans]
  • 43 kDa ISG15-specific protease
  • Synonym symbol(s) UBP43, ISG43
    TYPE functioning gene
    STRUCTURE 27.41 kb     11 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Promoter
    text structure IFNB response element and an AU-rich element in the promoter
    MAPPING cloned Y linked N status provisional
    Map cen - DGCR6 - USP18 - DGCR2 - TSSK2 - DGCR14 - GSCL - SLC25A1 - CLTCL1 - HIRA - MRPL40 - UFD1L - CDC45L - CLDN5 - GP1BB GP1BB - TBX1 - COMT - ZNF74 - qter
    Authors Schwer (00)
    Physical map
    CECR1 22q11.2 cat eye syndrome chromosome region, candidate 1 RPL32L2 22q11.1 ribosomal protein L32-like 2 CLCP1 22q11.2 Charot-Leyden crystal protein pseudogene 1 CECR2 22q11.2 cat eye syndrome chromosome region, candidate 2 SLC25A18 22q11.2 solute carrier family 25, (mitochondrial carrier), member 18 ATP6V1E1 22q11.21 ATPase, H+ transporting, lysosomal 31kDa, V1 subunit E isoform 1 BCL2L13 22q11.2 BCL2-like 13 (apoptosis facilitator) BID 22q11.21 BH3 interacting domain death agonist FLJ40542 22q11.21 hypothetical protein FLJ40542 LOC388843 22 LOC388843 KIAA0819 22q11.21 KIAA0819 protein MICAL3 22q11.21 flavoprotein oxidoreductase MICAL3 PEX26 22q11.21 peroxisome biogenesis factor 26 TUBA8 22q11 tubulin, alpha 8 USP18 22q11.21 ubiquitin specific protease 18 LOC391291 22 LOC391291 LOC388844 22 hypothetical gene supported by AK097777; AK128837; AK129567; BC040613 LOC220522 22q11.21 similar to Gamma-glutamyltranspeptidase 1 precursor (Gamma-glutamyltransferase 1) (CD224 antigen) LOC391292 22 similar to immunoglobulin superfamily, member 3; immunoglobin superfamily, member 3 LOC386610 22q11.21 E2F transcription factor 6 pseudogene LOC388845 22 LOC388845 LOC388846 22 similar to hypothetical protein DKFZp434P211.1 - human (fragments) LOC388847 22 similar to breakpoint cluster region isoform 1 LOC391293 22 LOC391293 LOC388848 22 LOC388848 DGCR6 22q11.21 DiGeorge syndrome critical region gene 6 PRODH 22q11.21 proline dehydrogenase (oxidase) 1 DGCR5 22q11 DiGeorge syndrome critical region gene 5 (non-coding) LOC391294 22 similar to POM121 membrane glycoprotein-like 1 LOC343830 22q11.21 similar to carbonic anhydrase XV DGCR2 22q11.21 DiGeorge syndrome critical region gene 2 LOC391295 22 similar to serine/threonine kinase FKSG81; spermiogenesis associated 4 STK22B 22q11.2 serine/threonine kinase 22B (spermiogenesis associated) DGCR14 22q11.21 DiGeorge syndrome critical region gene 14 GSCL 22q11.21 goosecoid-like SLC25A1 22q11.21 solute carrier family 25 (mitochondrial carrier; citrate transporter), member 1 CLTCL1 22q11.21 clathrin, heavy polypeptide-like 1 HIRA 22q11.21-q11.23 HIR histone cell cycle regulation defective homolog A (S. cerevisiae) MRPL40 22q11.2 mitochondrial ribosomal protein L40 LOC128977 22q11.21 hypothetical protein LOC128977 UFD1L 22q11.21 ubiquitin fusion degradation 1-like CDC45L 22q11.2 CDC45 cell division cycle 45-like (S. cerevisiae) CLDN5 22q11.21 claudin 5 (transmembrane protein deleted in velocardiofacial syndrome)
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    11 - 2037 43 372 - 2011 22170061
    - - - - - - 2011 22170061
  • N-terminal truncated isoform
  • shows different subcellular distribution compared with the full-length protein and enhanced deISGylation activity in the nucleus
    Type widely
       expressed in (based on citations)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    blood / hematopoieticthymus    
    Digestiveliver   highly
    Respiratoryrespiratory tractlarynx  highly
    Urinarybladder   highly
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    cell lineage hematopoiesis
    cell lines differentiated human melanoma cells
    at STAGE
    physiological period fetal
    Text spleen
  • short consensus sequences surrunding Cys (Cys box) and histidine (His box)
  • two other conserved domains commun to deubiquitin enzymes c
  • a critical hydrophobic patch in USP18 interacts with a hydrophobic region unique to ISG15, thus providing evidence that USP18's ISG15 specificity is mediated by a small interaction interface
    interspecies ortholog to murine Ubp43
    intraspecies paralog to ubiquitin specific protein proteases UBR
  • deubiquitinating protease family
  • peptidase C19 family
  • CATEGORY enzyme
    SUBCELLULAR LOCALIZATION     intracellular
    basic FUNCTION
  • deubiquitin enzyme, hydrolyzing isopeptide bonds between UB and folded protein domains such as additional UB moieties or target proteins
  • regulating BCR-ABL leukemogenesis via the type 1 interferon receptor signaling
  • G1P2 deconjugating protease having a role in innate immunity against viral infection
  • type I IFN-induced protein that deconjugates the ubiquitin-like modifier ISG15 from target proteins, was found to limit apoptotic susceptibility to IFNA or bortezomib
  • may significantly limit operation of the extrinsic apoptotic pathway triggered by type I IFN and drugs
  • IFN-inducible member of the ubiquitin-specific protease family
  • novel role in modulating conventional CD11b(+) dendritic cells development via its inhibitory effect on type I IFN signaling
  • plays a role in the negative regulation of interferon-alpha/beta signaling
  • removes ISG15 from conjugated proteins
  • key regulator of IFN signaling in beta cells, underlining the importance of this pathway in beta cell inflammation and death
  • roles of USP18 and USP20 in mediating virus-triggered signaling
  • CELLULAR PROCESS protein, ubiquitin dependent proteolysis
    cell organization/biogenesis
    a component
    small molecule
  • interacting with G1P2 (to maintain a critical cellular balance of G1P2-conjugated proteins in both healthy and stressed organism)
  • its overexpression elevated EGFR levels in a manner requiring the catalytic cysteine of USP18
  • potent regulator of EGFR protein expression
  • direct relationship was found between USP18 and CCND1 (but not cyclin E) expression
  • covalent linkage of ISG15 interferes with viral infection and USP18 is the major protease which specifically removes ISG15 from target proteins
  • USP18 is a transcriptional target of WT1, suggesting that increased expression of USP18 following WT1 loss contributes to Wilms tumorigenesis
  • cell & other
    activated by upregulated in normal tumor cells when treated with IFN beta, via the JAK/STAT pathway
    induced by INF1, genotoxic stress and viral infection
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    increases the resistance to oncogenic transformation by BCR-ABL
    tumoral     --over  
    increased in the malignant versus normal lung
    constitutional       loss of function
    induces inflammation by increasing the STAT signaling and exacerbates IFN-induced beta cell apoptosis by the mitochondrial pathway of cell death
    constitutional     --low  
    promotes up-regulation of MIR7-1, which in turn inhibits EGFR expression and the tumorigenic activity of cancer cells
    Variant & Polymorphism
    Candidate gene
    Therapy target
    novel candidate drug target for acute promyelocytic leukemia treatment
    antineoplastic target
    pharmacological inhibition of UBP43 may be of benefit in cancers and others diseases in which interferon is currently prescribed
    therapeutic potential of modulating USP18 levels in treating viral infection, especially for viruses sensitive to IFN signaling
  • deletion of murine Usp18 causes an increase in free and conjugated Isg15 at the feto-maternal interface and results in fetal death
  • bone marrow cells in Ubp43-deficient mice exhibited hypersensitivity to interferon-alpha/beta-mediated apoptosis