In the basal condition, mRNA expression of various ISGs, including Oas1a, Isg15, and Stat1, was significantly increased in ISGylation-deficient Ube1l−/− MEFs (Fig 1C); the same was observed for Ifnb1. Despite higher levels of basal STAT1 activity and anti-viral ISG expression, Ube1l−/− cells were more susceptible to viral infection (Fig 1D and 1E). Here, ISG15 is linked to viral infectious disease.