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Interferon-stimulated gene 15 (ISG15) is a 17 kDA secreted protein that in humans is encoded by the ISG15 gene.[1][2] 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.[3]

ISG15 shares several common properties with other ubiquitin-like proteins (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.


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[4]) 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.[5]


In pancreatic ductal adenocarcinoma, tumor-associated macrophages secrete ISG15 enhancing the phenotype of cancer stem cells in the tumor.[6]


  1. Blomstrom DC, Fahey D, Kutny R, Korant BD, Knight E Jr (Aug 1986). "Molecular characterization of the interferon-induced 15-kDa protein. Molecular cloning and nucleotide and amino acid sequence". J Biol Chem. 261 (19): 8811–6. PMID 3087979.
  2. "Entrez Gene: ISG15 ISG15 ubiquitin-like modifier".
  3. Morales, David J.; Lenschow, Deborah J. (December 2013). "The Antiviral Activities of ISG15". Journal of Molecular Biology. 425 (24): 4995–5008. doi:10.1016/j.jmb.2013.09.041. PMC 4090058.
  4. Woods, Matthew W. (et al) (17 November 2011). "Human HERC5 restricts an early stage of HIV-1 assembly by a mechanism correlating with the ISGylation of Gag". doi:10.1186/1742-4690-8-95. Retrieved 5 September 2011.
  5. Malakhov MP, Malakhova OA, Kim KI, Ritchie KJ, Zhang DE (Mar 2002). "UBP43 (USP18) specifically removes ISG15 from conjugated proteins". J Biol Chem. 277 (12): 9976–81. doi:10.1074/jbc.M109078200. PMID 11788588.
  6. Sainz, B.; Martin, B.; Tatari, M.; Heeschen, C.; Guerra, S. (3 November 2014). "ISG15 Is a Critical Microenvironmental Factor for Pancreatic Cancer Stem Cells". Cancer Research. 74 (24): 7309–7320. doi:10.1158/0008-5472.CAN-14-1354. PMID 25368022.

Further reading