ISG15 and infection: In general, it appears that viral proteases may have evolved to catalyze deISG15ylation reactions as a strategy to evade the host innate immune response, at least during early stages of infection.92, 93, 94 Interestingly, viral proteases catalyze deISG15ylation reactions at different sites, e.g. the leader protease of foot-and-mouth-disease virus (FMDV) is reported to catalyze the hydrolysis of ISG15 N-terminal to diglycine of the LRGG motif,82 opposed to SARS-CoV-2 PLpro which catalyzes the hydrolysis of ISG15 C-terminal to diglycine of the LRGG motif.