The ISG15 protein is a ubiquitin-like modifier induced by interferon, which induces modification and somehow inhibits cellular and viral proteins . Like ubiquitin , ISG15 is conjugated to lysines on numerous target proteins through its conserved C-terminal region. This reaction is mediated by specific E1-activating, E2-conjugating, and E3-ligase enzymes, all of which are also IFN-inducible.
Viruses escape from the antiviral activity of ISG15 by using different mechanisms. The influenza B virus NS1 protein for instance blocks the covalent linkage of ISG15 to its target proteins by directly interacting with ISG15. The papain-like protease from the severe acute respiratory syndrome coronavirus cleaves ISG15 derivatives.This resluts in inactivation of host antiviral protein MDA-5.