A strong induction of ISG15 in response to IFN treatment or viral infections implies an antiviral role for ISG15, yet surprisingly initial studies using vesicular stomatitis virus (VSV) and lymphocytic choriomeningitis virus (LCMV) demonstrated that ISG15 or UBE1L are dispensable for anti-viral immune responses in mice [10,11]. Here, IFNA1 is linked to viral infectious disease.