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FLASH GENE
Symbol ISG15 contributors: mct/pgu - updated : 30-05-2017
HGNC name ISG15 ubiquitin-like modifier
HGNC id 4053
Corresponding disease
IMD38 Immunodeficiency 38
Location 1p36.33      Physical location : 948.846 - 949.915
Synonym name
  • interferon-induced 17-kDa/15-kDa protein
  • ubiquitin cross-reactive protein precursor
  • interferon, alpha-inducible protein (clone IFI-15K)
  • Synonym symbol(s) UCRP, IFI15, G1P2 IMD38, IP17
    DNA
    TYPE functioning gene
    STRUCTURE 1.07 kb     2 Exon(s)
    regulatory sequence Promoter
    Binding site   enhancer
    text structure single
    MAPPING cloned Y linked N status provisional
    Map pter - D1S118 - ISG15 - D1S2336E - D1S282E - cen
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    2 - 685 17.7 165 - 1987 2440890
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   moderately
    Digestiveesophagus   highly
     intestinelarge intestinecolon moderately
     salivary gland   moderately
    Reproductivefemale systembreastmammary gland highly
     female systemuteruscervix highly
     female systemovary  moderately
     male systemprostate  highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Epithelial    
    Muscularsmooth  highly
    Muscularstriatum  highly
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Nervousneuron
    cell lineage lymphoid cells
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • two ubiquitin-like domains
  • only the C-terminal ubiquitin-like domain of ISG15 is recognized and essential for USP18 activity
  • HOMOLOGY
    interspecies homolog to rattus G1p2 (64.33 pc)
    Homologene
    FAMILY
  • ubiquitin family
  • CATEGORY immunity/defense , regulatory
    SUBCELLULAR LOCALIZATION extracellular
        intracellular
    intracellular,cytoplasm,cytosolic
    intracellular,nucleus,nucleoplasm
    text secreted
    basic FUNCTION
  • ubiquitin-like protein playing a role in immune response
  • may be associated with specialized functions in innate immune system
  • interferon-induced ubiquitin-like modifier, implicated in a variety of biological activities, which encompass antiviral defense, immune responses, and pregnancy
  • having not essential role for STAT1 signaling and responses against vesicular stomatitis and lymphocytic choriomeningitis virus
  • interacting with, and conjugated to its targets by UBE1L and UBE2E2
  • enhancing the innate antiviral response by inhibition of IRF3 degradation
  • involved in the conjugation of FLNB, leading to the release of RAC1, MEKK1 and MKK4 from the scaffold protein and thus blocking the JNK cascade activation
  • modifies proteins in a similar manner to ubiquitylation, and protein conjugation by ISG15 is termed ISGylation
  • removes ISG15 from conjugated proteins
  • plays an important role in innate immune responses
  • plays an important role in the regulation of macrophage responses
  • essential role of ISG15 in the cellular immune antiviral response leading to a better understanding of the antiviral responses triggered by ISG15 that may lead to the development of therapies against important human pathogens
  • ISG15 pathway implicated in the regulation of viral entry/uncoating
  • is a previously unrecognized support factor for Cancer stem cells (CSC) in the pancreatic ductal adenocarcinoma (PDAC) microenvironment with a key role in pathogenesis and progression
  • is an interferon-stimulated, linear di-ubiquitin-like protein, with anti-viral activity
  • ISG15-dependent restriction of Listeria infection, reinforcing the view that ISG15 is a key component of the innate immune response
  • unlike ISG15, ubiquitin and UBD are conjugated to a similar degree to newly translated and pre-existing proteins
  • CELLULAR PROCESS protein, ubiquitin dependent proteolysis
    cell communication
    PHYSIOLOGICAL PROCESS immunity/defense
    text antiviral response
    PATHWAY
    metabolism
    signaling
    cell-cell signaling
    a component
    INTERACTION
    DNA
    RNA
    small molecule
    protein
  • interacting with USP18 (to maintain a critical cellular balance of G1P2-conjugated proteins in both healthy and stressed organism)
  • EIF4E2 is modified by ISG15 and ISGylation of EIF4E2 may play an important role in cap structure-dependent translation control in immune responses
  • modification of UBE2N that suppresses its ubiquitin-conjugating activity
  • interacting with STAT1, SERPINA3G/SPI2A, JAK1, MAPK3/ERK1, PLCG1, EIF2AK2/PKR, MX1/MxA, RIG-1 and PPP2CB
  • interacting with USP21 (USP21 cleaves Ub polymers, and with reduced activity also targets ISG15, but is inactive against NEDD8)
  • covalent linkage of ISG15 interferes with viral infection and USP18 is the major protease which specifically removes ISG15 from target proteins
  • activation of double-stranded RNA-activated protein kinase (EIF2AK2) by interferon-stimulated gene 15 (ISG15) modification down-regulates protein translation
  • ISG15-dependent degradation of TP53 represents an alternative mechanism of controlling TP53 protein levels
  • ISG15 can modify ubiquitin, which is immobilized on its substrate, to form ISG15-ubiquitin mixed chains
  • 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
  • cell & other
    REGULATION
    induced by robustly induced by type I interferons, lipopolysaccharide (LPS), or viruses
    ASSOCIATED DISORDERS
    corresponding disease(s) IMD38
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS
  • deletion of murine Usp18 causes an increase in free and conjugated Isg15 at the feto-maternal interface and results in fetal death