InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: ISG15

Summary

InnateDB Protein

IDBP-84314.6

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

ISG15

Protein Name

ISG15 ubiquitin-like modifier

Synonyms

G1P2; hUCRP; IFI15; IP17; UCRP;

Species

Homo sapiens

Ensembl Protein

ENSP00000368699

InnateDB Gene

IDBG-84312 (ISG15)

Protein Structure

UniProt Annotation

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. 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. Its target proteins include IFIT1, MX1/MxA, PPM1B, UBE2L6, UBA7, CHMP5, CHMP2A, CHMP4B and CHMP6. Can also isgylate: EIF2AK2/PKR which results in its activation, DDX58/RIG-I 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 therby 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. {ECO:0000269PubMed:1373138, ECO:0000269PubMed:16009940, ECO:0000269PubMed:16112642, ECO:0000269PubMed:16428300, ECO:0000269PubMed:16434471, ECO:0000269PubMed:16872604, ECO:0000269PubMed:18305167, ECO:0000269PubMed:19270716, ECO:0000269PubMed:19357168, ECO:0000269PubMed:2005397, ECO:0000269PubMed:20133869, ECO:0000269PubMed:20308324, ECO:0000269PubMed:20639253, ECO:0000269PubMed:21543490, ECO:0000269PubMed:22693631, ECO:0000269PubMed:22859821, ECO:0000269PubMed:23229543, ECO:0000269PubMed:7526157, ECO:0000269PubMed:8550581}.

Subcellular Localization

Cytoplasm {ECO:0000269PubMed:22859821}. Secreted {ECO:0000269PubMed:22859821}. Note=Exists in three distinct states: free within the cell, released into the extracellular space, or conjugated to target proteins.

Disease Associations

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. {ECO:0000269PubMed:22859821, ECO:0000269PubMed:7490683}.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 244 experimentally validated interaction(s) in this database.
They are also associated with 5 interaction(s) predicted by orthology.

Experimentally validated
Total	244 [view]
Protein-Protein	214 [view]
Protein-DNA	30 [view]
Protein-RNA	0
DNA-DNA	0
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	5 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0005515	protein binding
GO:0031386	protein tag

Biological Process

GO:0016032	viral process
GO:0019221	cytokine-mediated signaling pathway
GO:0019941	modification-dependent protein catabolic process
GO:0031397	negative regulation of protein ubiquitination
GO:0032020	ISG15-protein conjugation
GO:0032480	negative regulation of type I interferon production
GO:0032649	regulation of interferon-gamma production
GO:0034340	response to type I interferon
GO:0042742	defense response to bacterium
GO:0045071	negative regulation of viral genome replication
GO:0045087	innate immune response (InnateDB)
GO:0045648	positive regulation of erythrocyte differentiation
GO:0051607	defense response to virus
GO:0060337	type I interferon signaling pathway