SARS-CoV-2 nucleocapsid protein binds host mRNAs and attenuates stress granules to impair host stress response
Syed Nabeel‐Shah, Hyunmin Lee, Nujhat Ahmed, Giovanni L. Burke, Shaghayegh Farhangmehr, Kanwal Ashraf, Shuye Pu, Ulrich Braunschweig, Guoqing Zhong, Hong Wei, Hua Tang, Jianyi Yang, Edyta Marcon, Benjamin J. Blencowe, Zhaolei Zhang, Jack Greenblatt
Abstract
Severe 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.