On the other hand, PLpro’s de-ISGylation activity on components of the IFN signaling pathway, such as melanoma differentiation-associated protein 5 (MDA5) and interferon responsive factor 3 (IRF3), critically impairs innate immunity’s capacity to combat viral infections (Shin et al., 2020; Liu et al., 2021). Here, IFIH1 is linked to viral infectious disease.