SARS-CoV-2 NSP14 suppresses RIG-I-mediated interferon production by dampening the interaction between DHX15 and RIG-I

Infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) imposes serious public health and economic burdens worldwide. SARS-CoV-2 has evolved a formidable arsenal of evasion strategies to outmaneuver innate immune responses. However, the role of nonstructural protein 14 (NSP14) of SARS-CoV-2 in RIG-I-mediated interferon production remains unclear. Here, we show that overexpression of NSP14 significantly suppresses type I/III interferon responses and downstream IFN-stimulated gene (ISG) expression, and inhibits TBK1 and IRF3 activation. The inhibitory effect of NSP14 on RIG-I-mediated antiviral signaling is dependent on its C-terminal N7-methyltransferase activity, but not on complex formation with NSP10. Mechanistically, we find that NSP14 interacts with DHX15, which was previously identified as a co-receptor of RIG-I. Further study shows that NSP14 dampens the interaction between DHX15 and RIG-I, thereby negatively regulating RIG-I-mediated antiviral signaling. Taken together, our findings provide insights into SARS-CoV-2 Nsp14-mediated evasion of host innate immunity. SARS-CoV-2 NSP14 inhibited RIG-I-mediated interferon production dependent on its N7-MTase. DHX15 cooperated with RIG-I to enhance RNA virus-induced signaling and was targeted by NSP14. NSP14 interfered with the interaction between DHX15 and RIG-I.