Interferon-induced helicase C domain-containing protein 1 (IFIH1, also known as MDA5) functions as a cytoplasmic sensor of viral RNA to induce production of type I interferons and proinflammatory cytokines. ISGylation at K23 and K43 in the N-terminal caspase activation and recruitment domains (CARDs) of IFIH1 promotes oligomerization and signalig of IFIH1 in human cells upon infections caused by a range of viruses including coronaviruses, flaviviruses and picornaviruses (Liu GQ et al. 2021). SARS-CoV-2 infection activates the type I IFN production in a IFIH1-dependent manner (Yin X et al. 2021; Liu GQ et al. 2021). The SARS-CoV-2 papain-like protease (nsp3) binds to IFIH1 upon co-expression in human embryonic kidney 293T cells (HEK293T) (Liu GQ et al. 2021). This interaction antagonizes the antiviral host response by removing ISG15 from IFIH1 (Liu GQ et al. 2021). Viral nsp3 was found to interact with endogenous IFIH1 (MDA5) in SARS-CoV-2-infected human lung carcinoma A549 cells expressing human ACE2 (Liu GQ et al. 2021). In addition, papain-like proteases derived from other coronaviruses, SARS-CoV-1, MERS-CoV, murine hepatitis virus (MHV), and human HCoV-NL63 (NL63) also target IFIH1 to reduce ISGylation of IFIH1 upon co-expression of viral proteins and IFIH1 in HEK293T (Liu GQ et al. 2021). This Reactome event shows deISGylation of IFIH1 by SARS-COV-2 nsp3.