Interferon-induced 17 kDa protein is a protein that in humans is encoded by the ISG15gene. 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) 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. 
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. PMID16407192.
Loeb KR, Haas AL (1992). "The interferon-inducible 15-kDa ubiquitin homolog conjugates to intracellular proteins". J. Biol. Chem.267 (11): 7806–13. PMID1373138.
Clauss IM, Wathelet MG, Szpirer J et al. (1990). "Chromosomal localization of two human genes inducible by interferons, double-stranded RNA, and viruses". Cytogenet. Cell Genet.53 (2–3): 166–8. doi:10.1159/000132920. PMID1695131.
Knight E, Cordova B (1991). "IFN-induced 15-kDa protein is released from human lymphocytes and monocytes". J. Immunol.146 (7): 2280–4. PMID2005397.
Haas AL, Ahrens P, Bright PM, Ankel H (1987). "Interferon induces a 15-kilodalton protein exhibiting marked homology to ubiquitin". J. Biol. Chem.262 (23): 11315–23. PMID2440890.
Feltham N, Hillman M, Cordova B et al. (1989). "A 15-kD interferon-induced protein and its 17-kD precursor: expression in Escherichia coli, purification, and characterization". J. Interferon Res.9 (5): 493–507. doi:10.1089/jir.1989.9.493. PMID2477469.
Knight E, Fahey D, Cordova B et al. (1988). "A 15-kDa interferon-induced protein is derived by COOH-terminal processing of a 17-kDa precursor". J. Biol. Chem.263 (10): 4520–2. PMID3350799.
Narasimhan J, Potter JL, Haas AL (1996). "Conjugation of the 15-kDa interferon-induced ubiquitin homolog is distinct from that of ubiquitin". J. Biol. Chem.271 (1): 324–30. doi:10.1074/jbc.271.1.324. PMID8550581.
D'Cunha J, Ramanujam S, Wagner RJ et al. (1996). "In vitro and in vivo secretion of human ISG15, an IFN-induced immunomodulatory cytokine". J. Immunol.157 (9): 4100–8. PMID8892645.
Smith JK, Siddiqui AA, Krishnaswamy GA et al. (1999). "Oral use of interferon-alpha stimulates ISG-15 transcription and production by human buccal epithelial cells". J. Interferon Cytokine Res.19 (8): 923–8. doi:10.1089/107999099313460. PMID10476939.
Bebington C, Doherty FJ, Fleming SD (1999). "Ubiquitin cross-reactive protein gene expression is increased in decidualized endometrial stromal cells at the initiation of pregnancy". Mol. Hum. Reprod.5 (10): 966–72. doi:10.1093/molehr/5.10.966. PMID10508226.
Nyman TA, Matikainen S, Sareneva T et al. (2000). "Proteome analysis reveals ubiquitin-conjugating enzymes to be a new family of interferon-alpha-regulated genes". Eur. J. Biochem.267 (13): 4011–9. doi:10.1046/j.1432-1327.2000.01433.x. PMID10866800.
Malakhov MP, Malakhova OA, Kim KI et al. (2002). "UBP43 (USP18) specifically removes ISG15 from conjugated proteins". J. Biol. Chem.277 (12): 9976–81. doi:10.1074/jbc.M109078200. PMID11788588.
Meraro D, Gleit-Kielmanowicz M, Hauser H, Levi BZ (2002). "IFN-stimulated gene 15 is synergistically activated through interactions between the myelocyte/lymphocyte-specific transcription factors, PU.1, IFN regulatory factor-8/IFN consensus sequence binding protein, and IFN regulatory factor-4: characterization of a new subtype of IFN-stimulated response element". J. Immunol.168 (12): 6224–31. doi:10.4049/jimmunol.168.12.6224. PMID12055236.
Padovan E, Terracciano L, Certa U et al. (2002). "Interferon stimulated gene 15 constitutively produced by melanoma cells induces e-cadherin expression on human dendritic cells". Cancer Res.62 (12): 3453–8. PMID12067988.