Conserved Antagonism of cGAS-STING Signaling by NSP2 Proteins from SARS-CoV-2 and SARSr-CoV-2

Despite the high risk of host-shift associated with SARSr-CoV-2, the extent to which these viruses share similar or distinct molecular mechanisms in antagonizing host innate immune responses, compared to SARS-CoV-2, remains largely unexplored. RIG-Ⅰ-like receptors (RLRs) and cGAS-STING signaling pathways function as critical innate immune sensors that detect viral infection and trigger IFN-Ⅰ production to restrict viral replication.Whether SARS-CoV-2 modulates the cGAS-STING pathway remains incompletely understood. Here, we demonstrate that SARSr-CoV-2 and SARS-CoV-2 NSP2 target STING to suppress type Ⅰ IFN production. Mechanistically, SARSr-CoV-2 and SARS-CoV-2 NSP2 interact with STING and impair STING oligomerization and aggregation. Furthermore, NSP2 attenuates the association between STING and TBK1 and inhibits STING translocation from the endoplasmic reticulum to the Golgi apparatus. As a consequence, NSP2 suppresses cGAS-STING-mediated phosphorylation of TBK1 and IRF3, impairs IRF3 nuclear translocation, and ultimately reduces type Ⅰ IFN production. Taken together, these findings suggest that SARSr-CoV-2 and SARS-CoV-2 NSP2 impair the cGAS-STING signaling pathway and provide insights for developing antiviral strategies against coronavirus.