MRC Protein Phosphorylation and Ubiquitylation Seminar
The interferon (IFN)-stimulated gene 15 (ISG15) encodes one of the most abundant proteins induced by interferon, and its expression is associated with antiviral immunity. This includes inhibition of viral protein secretion, increased antigen presentation and metabolic reprogramming. Many viruses have in turn co-evolved with their host to encode de-ISGylating activities to antagonize this effect. Our results show that while infection by viruses such as influenza and Zika is accompanied by increased substrate ISGylation, SARS-CoV-2 actively triggers de-ISGylation to generate free secreted ISG15, which contributes to pro-inflammatory responses. Collectively, our data indicate that altering free versus conjugated ISG15 likely contributes to aberrant immune responses and drives immunopathology during virus infection.