ISG15

ISG15
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1Z2M, 2HJ8, 3PHX, 3PSE, 3R66, 3RT3, 3SDL
Identifiers
Aliases	ISG15, G1P2, IFI15, IP17, UCRP, hUCRP, IMD38, ISG15 ubiquitin-like modifier, ISG15 ubiquitin like modifier
External IDs	OMIM: 147571; MGI: 1855694; HomoloGene: 48326; GeneCards: ISG15; OMA:ISG15 - orthologs
Gene location (Human) Chr. Chromosome 1 (human) Band 1p36.33 Start 1,001,138 bp End 1,014,540 bp
Gene location (Mouse) Chr. Chromosome 4 (mouse) Band 4 E2|4 Start 156,283,912 bp End 156,285,253 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in decidua periodontal fiber testicle granulocyte amniotic fluid lateral nuclear group of thalamus trigeminal ganglion stromal cell of endometrium monocyte amygdala Top expressed in bone marrow jejunum granulocyte placenta colon thymus spleen duodenum ileum esophagus More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein binding protein tag integrin binding Cellular component cytoplasm cytosol nucleoplasm extracellular region Biological process immune system process regulation of interferon-gamma production negative regulation of protein ubiquitination negative regulation of viral genome replication defense response to virus type I interferon signaling pathway response to type I interferon translesion synthesis negative regulation of type I interferon production viral process innate immune response modification-dependent protein catabolic process positive regulation of bone mineralization ISG15-protein conjugation defense response to bacterium positive regulation of erythrocyte differentiation response to bacterium integrin-mediated signaling pathway Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 9636 100038882 Ensembl ENSG00000187608 ENSMUSG00000035692 UniProt P05161 Q64339 RefSeq (mRNA) NM_005101 NM_015783 RefSeq (protein) NP_005092 NP_056598 Location (UCSC) Chr 1: 1 – 1.01 Mb Chr 4: 156.28 – 156.29 Mb PubMed search
Wikidata
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Interferon-stimulated gene 15 (ISG15) is a 17 kDA secreted protein that in humans is encoded by the ISG15 gene. The main cellular function of the protein is ISGylation, its covalent addition to cytoplasmic and nuclear proteins, similar to ubiquitination. In addition, ISG15 has anti-viral activity.

ISG15 shares several common properties with other ubiquitin-like molecules (UBLs), but its activity is tightly regulated by specific signaling pathways that have a role in innate immunity. ISG15 was identified as an interferon stimulated gene (ISG) since its expression is induced in response to type I interferons or lipopolysaccharide treatment. Upon interferon treatment, ISG15 can be detected in both free and conjugated forms, and is secreted from monocytes and lymphocytes where it can function as a cytokine. In the cell, ISG15 co-localizes with intermediate filaments and ISGylation may modulate the JAK-STAT pathway or certain aspects of neurological disease. It is also known as UCRP (ubiquitin cross-reactive protein) since it contains 2 tandem ubiquitin homology domains and is cross-reactive with ubiquitin antibodies. In contrast to other UBLs, ISG15 has not been identified in lower eukaryotes (yeast, nematode, insects, plants) indicating its role in specialized functions.

ISGylation

The mechanism of ISGylation and deISGylation is similar to that of ubiquitin, although the complete system components have not yet been identified. The activating E1 enzyme (UBE1L) charges ISG15 by forming a high-energy thiolester intermediate and transfers it to the UbcH8 E2 protein. UbcH8 has been identified as the major E2 for ISGylation, although it also functions in ubiquitination. The E2 protein subsequently transfers the ISG15 to specific E3 ligases (Herc5) and relevant intracellular substrates. Only one deconjugating protease with specificity to ISG15 has been identified to date: UBP43 (a member of the USP family) cleaves ISG15-peptide fusions and also removes ISG15 (deISGylation) from native conjugates.

Pathology

In pancreatic ductal adenocarcinoma, tumor-associated macrophages secrete ISG15 enhancing the phenotype of cancer stem cells in the tumor.

Further reading

• Dastur A, Beaudenon S, Kelley M, Krug RM, Huibregtse JM (February 2006). "Herc5, an interferon-induced HECT E3 enzyme, is required for conjugation of ISG15 in human cells". J. Biol. Chem. 281 (7): 4334–8. doi:10.1074/jbc.M512830200. PMID 16407192.{{cite journal}}: CS1 maint: unflagged free DOI (link)
• Bektas N, Noetzel E, Veeck J, et al. (2008). "The ubiquitin-like molecule interferon-stimulated gene 15 (ISG15) is a potential prognostic marker in human breast cancer". Breast Cancer Res. 10 (4): R58. doi:10.1186/bcr2117. PMC 2575531. PMID 18627608.{{cite journal}}: CS1 maint: unflagged free DOI (link)