P05161 · ISG15_HUMAN

  • Protein
    Ubiquitin-like protein ISG15
  • Gene
    ISG15
  • Status
    UniProtKB reviewed (Swiss-Prot)
  • Amino acids
  • Protein existence
    Evidence at protein level
  • Annotation score
    5/5

Function

function

Ubiquitin-like protein which plays a key role in the innate immune response to viral infection either via its conjugation to a target protein (ISGylation) or via its action as a free or unconjugated protein (PubMed:27564865).
ISGylation involves a cascade of enzymatic reactions involving E1, E2, and E3 enzymes which catalyze the conjugation of ISG15 to a lysine residue in the target protein (PubMed:33727702).
Its target proteins include IFIT1, MX1/MxA, PPM1B, UBE2L6, UBA7, CHMP5, CHMP2A, CHMP4B and CHMP6. Isgylation of the viral sensor IFIH1/MDA5 promotes IFIH1/MDA5 oligomerization and triggers activation of innate immunity against a range of viruses, including coronaviruses, flaviviruses and picornaviruses (PubMed:33727702).
Can also isgylate: EIF2AK2/PKR which results in its activation, RIGI which inhibits its function in antiviral signaling response, EIF4E2 which enhances its cap structure-binding activity and translation-inhibition activity, UBE2N and UBE2E1 which negatively regulates their activity, IRF3 which inhibits its ubiquitination and degradation and FLNB which prevents its ability to interact with the upstream activators of the JNK cascade thereby inhibiting IFNA-induced JNK signaling. Exhibits antiviral activity towards both DNA and RNA viruses, including influenza A, HIV-1 and Ebola virus. Restricts HIV-1 and ebola virus via disruption of viral budding. Inhibits the ubiquitination of HIV-1 Gag and host TSG101 and disrupts their interaction, thereby preventing assembly and release of virions from infected cells. Inhibits Ebola virus budding mediated by the VP40 protein by disrupting ubiquitin ligase activity of NEDD4 and its ability to ubiquitinate VP40. ISGylates influenza A virus NS1 protein which causes a loss of function of the protein and the inhibition of virus replication. The secreted form of ISG15 can: induce natural killer cell proliferation, act as a chemotactic factor for neutrophils and act as a IFN-gamma-inducing cytokine playing an essential role in antimycobacterial immunity. The secreted form acts through the integrin ITGAL/ITGB2 receptor to initiate activation of SRC family tyrosine kinases including LYN, HCK and FGR which leads to secretion of IFNG and IL10; the interaction is mediated by ITGAL (PubMed:29100055).

Features

Showing features for site.

TypeIDPosition(s)Description
Site153Interacts with activating enzyme

GO annotations

AspectTerm
Cellular Componentcytoplasm
Cellular Componentcytosol
Cellular Componentextracellular region
Cellular Componentnucleoplasm
Molecular Functionintegrin binding
Molecular Functionprotein tag activity
Molecular Functionubiquitin protein ligase binding
Biological Processdefense response to bacterium
Biological Processdefense response to virus
Biological Processinnate immune response
Biological Processintegrin-mediated signaling pathway
Biological ProcessISG15-protein conjugation
Biological Processmodification-dependent protein catabolic process
Biological Processnegative regulation of protein ubiquitination
Biological Processnegative regulation of type I interferon-mediated signaling pathway
Biological Processnegative regulation of viral genome replication
Biological Processpositive regulation of bone mineralization
Biological Processpositive regulation of erythrocyte differentiation
Biological Processpositive regulation of interferon-beta production
Biological Processpositive regulation of interleukin-10 production
Biological Processpositive regulation of protein oligomerization
Biological Processpositive regulation of type II interferon production
Biological Processprotein localization to mitochondrion
Biological Processregulation of type II interferon production
Biological Processresponse to type I interferon
Biological Processresponse to virus

Keywords

Enzyme and pathway databases

Names & Taxonomy

Protein names

  • Recommended name
    Ubiquitin-like protein ISG15
  • Alternative names
    • Interferon-induced 15 kDa protein
    • Interferon-induced 17 kDa protein (IP17)
    • Ubiquitin cross-reactive protein (hUCRP)

Gene names

    • Name
      ISG15
    • Synonyms
      G1P2, UCRP

Organism names

  • Taxonomic identifier
  • Taxonomic lineage
    Eukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo

Accessions

  • Primary accession
    P05161
  • Secondary accessions
    • Q5SVA4
    • Q7Z2G2
    • Q96GF0

Proteomes

Organism-specific databases

Subcellular Location

Cytoplasm
Secreted
Note: Exists in three distinct states: free within the cell, released into the extracellular space, or conjugated to target proteins.

Keywords

Disease & Variants

Involvement in disease

Immunodeficiency 38, with basal ganglia calcification (IMD38)

  • Note
    • The disease is caused by variants affecting the gene represented in this entry
  • Description
    A primary immunodeficiency predisposing individuals to severe clinical disease upon infection with weakly virulent mycobacteria, including Mycobacterium bovis Bacille Calmette-Guerin (BCG) vaccines. Patients are also susceptible to Salmonella and Mycobacterium tuberculosis infections. Affected individuals have intracranial calcification.
  • See also
    MIM:616126

Features

Showing features for mutagenesis, natural variant.

TypeIDPosition(s)Description
Mutagenesis44Does not affect ISG15 signaling, interaction with ITGAL or activation of SRC family tyrosine kinases.
Natural variantVAR_01618183in dbSNP:rs1921
Mutagenesis83Does not affect ISG15 signaling, interaction with ITGAL or activation of SRC family tyrosine kinases.
Mutagenesis96Reduces ISG15 signaling. Strongly reduces ISG15 signaling and abolishes interaction with ITGAL and activation of SRC family tyrosine kinases; when associated with D-102.
Mutagenesis99Strongly reduces ISG15 signaling and abolishes interaction with ITGAL.
Mutagenesis101Strongly reduces ISG15 signaling and abolishes interaction with ITGAL and activation of SRC family tyrosine kinases.
Mutagenesis102Reduces ISG15 signaling. Strongly reduces ISG15 signaling and abolishes interaction with ITGAL and activation of SRC family tyrosine kinases; when associated with L-96.
Mutagenesis103Strongly reduces ISG15 signaling and abolishes interaction with ITGAL.

Variants

We now provide the "Disease & Variants" viewer in its own tab.

The viewer provides 202 variants from UniProt as well as other sources including ClinVar and dbSNP.

Go to variant viewer

Organism-specific databases

Miscellaneous

Genetic variation databases

PTM/Processing

Features

Showing features for initiator methionine, chain, modified residue, disulfide bond, cross-link, propeptide.

TypeIDPosition(s)Description
Initiator methionine1Removed
ChainPRO_00000359862-157Ubiquitin-like protein ISG15
Modified residue78S-nitrosocysteine; alternate
Disulfide bond78Interchain (with C-87 in UBE2N); alternate
Cross-link157Glycyl lysine isopeptide (Gly-Lys) (interchain with K-? in acceptor proteins)
PropeptidePRO_0000035987158-165Removed in mature form

Post-translational modification

S-nitrosylation decreases its dimerization, thereby increasing the availability as well as the solubility of monomeric ISG15 for its conjugation to cellular proteins.
Induced as an inactive, precursor protein that is cleaved by specific proteases to expose the C-terminal diglycine (LRLRGG) motif. This motif is essential not only for its conjugation to substrates but also for its recognition by the relevant processing proteases.

Keywords

Proteomic databases

PTM databases

Expression

Tissue specificity

Detected in lymphoid cells, striated and smooth muscle, several epithelia and neurons. Expressed in neutrophils, monocytes and lymphocytes. Enhanced expression seen in pancreatic adenocarcinoma, endometrial cancer, and bladder cancer, as compared to non-cancerous tissue. In bladder cancer, the increase in expression exhibits a striking positive correlation with more advanced stages of the disease.

Induction

Strongly induced upon exposure to type I interferons, viruses, LPS, and other stresses, including certain genotoxic stresses.

Gene expression databases

Organism-specific databases

Interaction

Subunit

Homodimer; disulfide-linked (PubMed:2440890).
Interacts with, and is conjugated to its targets by UBE1L (E1 enzyme) and UBE2E2 (E2 enzyme) (PubMed:11157743, PubMed:15131269).
Interacts with NEDD4 (PubMed:18305167).
(Microbial infection) Interacts with vaccinia virus protein E3.
(Microbial infection) Interaction with influenza B NS1 protein inhibits its conjugation.
(Microbial infection) Interacts (via C-terminus) with Crimean-Congo hemorrhagic fever virus (CCHFV) RNA-directed RNA polymerase L (via N-terminus); the deISGylase activity of the viral protein interferes with antiviral signaling pathways mediated by NF-kappaB and IRF signalings.
(Microbial infection) Interacts with human cytomegalovirus protein UL26; this interaction inhibits global protein ISGylation.

Binary interactions

Protein-protein interaction databases

Miscellaneous

Family & Domains

Features

Showing features for domain, motif, region.

TypeIDPosition(s)Description
Domain2-78Ubiquitin-like 1
Domain79-157Ubiquitin-like 2
Motif152-157LRLRGG
Region153-157Involved in the ligation of specific target proteins

Domain

Both the Ubiquitin-like 1 and Ubiquitin-like 2 domains are required for its efficient conjugation to cellular proteins. The two domains play different roles in the ISGylation pathway: Ubiquitin-like 2 domain is necessary for the first two steps allowing the linking of ISG15 to the E1 and E2 enzymes while Ubiquitin-like 1 domain is essential for the final, E3-mediated transfer of ISG15, from the E2 to the Lys of the target protein (PubMed:18356159).

Keywords

Phylogenomic databases

Family and domain databases

Sequence

  • Sequence status
    Complete
  • Sequence processing
    The displayed sequence is further processed into a mature form.
  • Length
    165
  • Mass (Da)
    17,888
  • Last updated
    2007-01-23 v5
  • Checksum
    B6858A15AB0FFFDE
MGWDLTVKMLAGNEFQVSLSSSMSVSELKAQITQKIGVHAFQQRLAVHPSGVALQDRVPLASQGLGPGSTVLLVVDKCDEPLSILVRNNKGRSSTYEVRLTQTVAHLKQQVSGLEGVQDDLFWLTFEGKPLEDQLPLGEYGLKPLSTVFMNLRLRGGGTEPGGRS

Computationally mapped potential isoform sequences

There are 2 potential isoforms mapped to this entry

View all
EntryEntry nameGene nameLength
A0A096LNZ9A0A096LNZ9_HUMANISG15143
A0A096LPJ4A0A096LPJ4_HUMANISG15157

Features

Showing features for sequence conflict.

TypeIDPosition(s)Description
Sequence conflict35in Ref. 2; AAA36128

Keywords

Sequence databases

Nucleotide SequenceProtein SequenceMolecule TypeStatus
M13755
EMBL· GenBank· DDBJ
AAA36038.1
EMBL· GenBank· DDBJ
mRNA
M21786
EMBL· GenBank· DDBJ
AAA36128.1
EMBL· GenBank· DDBJ
Genomic DNA
AY168648
EMBL· GenBank· DDBJ
AAN86983.1
EMBL· GenBank· DDBJ
mRNA
BT007297
EMBL· GenBank· DDBJ
AAP35961.1
EMBL· GenBank· DDBJ
mRNA
AL645608
EMBL· GenBank· DDBJ
-Genomic DNA No translation available.
CH471183
EMBL· GenBank· DDBJ
EAW56295.1
EMBL· GenBank· DDBJ
Genomic DNA
BC009507
EMBL· GenBank· DDBJ
AAH09507.1
EMBL· GenBank· DDBJ
mRNA

Genome annotation databases

Similar Proteins

Disclaimer

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