From Wikipedia, the free encyclopedia
Jump to: navigation, search
ISG15 ubiquitin-like modifier
Protein ISG15 PDB 1z2m.png
PDB rendering based on 1z2m.
Available structures
PDB Ortholog search: PDBe, RCSB
Symbols ISG15 ; G1P2; IFI15; IMD38; IP17; UCRP; hUCRP
External IDs OMIM147571 HomoloGene48326 GeneCards: ISG15 Gene
RNA expression pattern
PBB GE ISG15 205483 s at tn.png
More reference expression data
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:
156.2 – 156.2 Mb
PubMed search [1] [2]

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 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.


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. 
  4. ^  Missing or empty |title= (help)
  5. ^ "Boston Biochem ISG15 Overview". Archived from the original on 2008-05-02. Retrieved 2008-05-21. 
  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. 

Further reading[edit]