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Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is a poor inducer of innate antiviral immunity, and the underlying mechanism still needs further investigation. Here, we reported that SARS‐CoV‐2 NSP7 inhibited… Click to show full abstract
Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is a poor inducer of innate antiviral immunity, and the underlying mechanism still needs further investigation. Here, we reported that SARS‐CoV‐2 NSP7 inhibited the production of type I and III interferons (IFNs) by targeting the RIG‐I/MDA5, Toll‐like receptor (TLR3)‐TRIF, and cGAS‐STING signaling pathways. SARS‐CoV‐2 NSP7 suppressed the expression of IFNs and IFN‐stimulated genes induced by poly (I:C) transfection and infection with Sendai virus or SARS‐CoV‐2 virus‐like particles. NSP7 impaired type I and III IFN production activated by components of the cytosolic dsRNA‐sensing pathway, including RIG‐I, MDA5, and MAVS, but not TBK1, IKKε, and IRF3‐5D, an active form of IRF3. In addition, NSP7 also suppressed TRIF‐ and STING‐induced IFN responses. Mechanistically, NSP7 associated with RIG‐I and MDA5 prevented the formation of the RIG‐I/MDA5−MAVS signalosome and interacted with TRIF and STING to inhibit TRIF‐TBK1 and STING‐TBK1 complex formation, thus reducing the subsequent IRF3 phosphorylation and nuclear translocation that are essential for IFN induction. In addition, ectopic expression of NSP7 impeded innate immune activation and facilitated virus replication. Taken together, SARS‐CoV‐2 NSP7 dampens type I and III IFN responses via disruption of the signal transduction of the RIG‐I/MDA5−MAVS, TLR3‐TRIF, and cGAS‐STING signaling pathways, thus providing novel insights into the interactions between SARS‐CoV‐2 and innate antiviral immunity.