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FLASH GENE
Symbol ISG15 contributors: mct/pgu - updated : 30-05-2017
HGNC name ISG15 ubiquitin-like modifier
HGNC id 4053
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 is a ubiquitin-like protein transcriptionally regulated by IFNA1 which shows antivirus and antitumor activities
  • ISG15 inhibits IFNA1-resistant liver cancer cell growth
  • 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