摘要：SummarySevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid (N) protein is essential for viral replication, making it a promising target for antiviral drug and vaccine development. SARS-CoV-2 infected patients exhibit an uncoordinated immune response; however, the underlying mechanistic details of this imbalance remain obscure. Here, starting from a functional proteomics workflow, we cataloged the protein–protein interactions of SARS-CoV-2 proteins, including an evolutionarily conserved specific interaction of N with the stress granule resident proteins G3BP1 and G3BP2. N localizes to stress granules and sequesters G3BPs away from their typical interaction partners, thus attenuating stress granule formation. We found that N binds directly to host mRNAs in cells, with a preference for 3′ UTRs, and modulates target mRNA stability. We show that the N protein rewires the G3BP1 mRNA-binding profile and suppresses the physiological stress response of host cells, which may explain the imbalanced immune response observed in SARS-CoV-2 infected patients.Graphical abstractDisplay OmittedHighlights•AP-MS identifies 753 viral-host protein–protein interactions for 27 SARS-CoV-2 proteins•SARS-CoV-2 N protein sequesters G3BP1/2 and attenuates stress granule formation•N binds directly to mRNAs, rewires G3BP1 mRNA targets, and modulates mRNA stability•SARS-CoV-2 N dampens host stress response via altering posttranscriptional programsMolecular biology; Virology; Cell biology; Proteomics;
