Viral deISGylation holds the key to the metabolic kingdom.

The interferon-induced modification of cellular and viral proteins by ISG15 inhibits viral infection and is reversed by virus-encoded deISGylases, but the broad physiological impacts of this host-pathogen clash remain unclear. In this issue of Immunity, Zhu et al. reveal that ISG15 modification broadly restricts key metabolic pathways that deISGylation relieves to promote viral replication.