LAUSR

SARS‐CoV‐2 has developed a variety of approaches to counteract host innate antiviral immunity to facilitate its infection, replication and pathogenesis, but the molecular mechanisms that it employs are still not been fully understood. Here, we found that SARS‐CoV‐2 NSP8 inhibited the production of type I and III interferons (IFNs) by acting on RIG‐I/MDA5 and the signaling molecules TRIF and STING. Overexpression of NSP8 downregulated the expression of type I and III IFNs stimulated by poly (I:C) transfection and infection with SeV and SARS‐CoV‐2. In addition, NSP8 impaired IFN expression triggered by overexpression of the signaling molecules RIG‐I, MDA5, and MAVS, instead of TBK1 and IRF3‐5D, an active form of IRF3. From a mechanistic view, NSP8 interacts with RIG‐I and MDA5, and thereby prevents the assembly of the RIG‐I/MDA5‐MAVS signalosome, resulting in the impaired phosphorylation and nuclear translocation of IRF3. NSP8 also suppressed the TRIF‐ and STING‐ induced IFN expression by directly interacting with them. Moreover, ectopic expression of NSP8 promoted virus replications. Taken together, SARS‐CoV‐2 NSP8 suppresses type I and III IFN responses by disturbing the RIG‐I/MDA5−MAVS complex formation and targeting TRIF and STING signaling transduction. These results provide new insights into the pathogenesis of COVID‐19.