ISG15 in cancer: Beyond ubiquitin-like protein

ISG15, the product of interferon (IFN)-stimulated gene 15, is the first identified ubiquitin-like protein (Ubl), playing roles not only as an unconjugated form but also as a covalently conjugated form onto a target protein. ISG15 is not present in lower eukaryotes such as yeast, nematode (Caenorhabditis), or insect (Drosophila), indicating that the functions of ISG15 and ISG15 conjugation (ISGylation) are restricted to higher eukaryotes and have evolved with IFN signaling. Despite the highlighted complexity of ISG15 and ISGylation, increasing evidences have been emerging that ISG15 and ISGylation are implicated in a variety of pivotal cellular processes, involving protein translation, autophagy, exosome secretion, DNA repair, and immune modulation, which emphasizes the necessity of re-evaluation of ISG15 and ISGylation. In this review, we highlight current knowledge in the molecular understanding and physiological relevance of ISG15 and ISGylation and discuss new insights into how ISG15 is implicated in the pathogenesis of cancer, which could contribute to therapeutic intervention in cancer.