Interferon-induced ISG15 pathway: an ongoing virus–host battle

ISG15 is an interferon (IFN)-induced ubiquitin-like protein that is conjugated to target proteins via the sequential action of three enzymes that are also induced by IFN. Unlike ubiquitin, which is highly conserved, the sequence of ISG15 varies between species. ISG15 conjugation inhibits many viruses, and free (unconjugated) ISG15 can also act as an antiviral protein. In this review, we focus on the antiviral role of ISG15 conjugation and on countermeasures employed by several viruses. The countermeasure by influenza B virus is unique in that it exhibits species specificity. Only the antiviral activity of human and non-human primate ISG15s can be blocked, providing one possible explanation for the restriction of influenza B virus to humans.