SARS-CoV-2 main protease suppresses type I interferon production by preventing nuclear translocation of phosphorylated IRF3

Suppression of type I interferon (IFN) response is one pathological outcome of the infection of highly pathogenic human coronaviruses. To effect this, severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2 encode multiple IFN antagonists. In this study, we reported on the IFN antagonism of SARS-CoV-2 main protease NSPS. NSPS proteins of both SARS-CoV and SARS-CoV-2 counteracted Sendai virus-induced IFN production. NSPS variants G15S and K90R commonly seen in circulating strains of SARS-CoV-2 retained the IFN-antagonizing property. The suppressive effect of NSPS on IFN-beta gene transcription induced by RIG-I, MAYS, TBK1 and IKKE suggested that NSPS likely acts at a step downstream of IRF3 phosphorylation in the cytoplasm. NSPS did not influence steady-state expression or phosphorylation of IRF3, suggesting that IRF3, regardless of its phosphorylation state, might not be the substrate of NSPS protease. However, nuclear translocation of phosphorylated IRF3 was severely compromised in NSPS-expressing cells. Taken together, our work revealed a new mechanism by which NSPS proteins encoded by SARS-CoV and SARS-CoV-2 antagonize IFN production by retaining phosphorylated IRF3 in the cytoplasm. Our findings have implications in rational design and development of antiviral agents against SARS-CoV-2.

Automated summary

Both SARS-CoV and SARS-CoV-2 use NSPS proteins to antagonize IFN production, with variants like G15S and K90R retaining this antagonistic property.