SARS-CoV-2 Nucleocapsid Protein Impairs SG Assembly by Partitioning into G3BP Condensate

SARS-CoV-2, the causative agent of coronavirus disease 2019 (COVID-19), has posed a huge threat to global health and economy. A key to tackle this pandemic is to understand how SARS-CoV-2 manages to outsmart antiviral defense mechanisms. Stress granules (SGs), assembled during stress and functioning to sequester mRNA, are part of the antiviral response. Here, we show the SARS-CoV-2 N protein, an RNA binding protein involved in viral RNA replication and transcription, interacts with RNA-binding protein G3BP (the core proteins in SGs) and inhibits SG assembly in vivo, both effects requiring the RNA binding domain in N protein. Furthermore, N protein undergoes liquid-liquid phase separation (LLPS) and partitions into G3BP droplets in an RNA-dependent manner in vitro. This study suggests that N protein-mediated suppression of SG assembly is an important step in the pathogenesis of COVID-19, which has obvious therapeutic implications. Funding: This work is supported by National Science Foundation of China (81830004) and Local Grant (608285568031). Conflict of Interest: The authors declare no competing interests. Ethical Approval: The ShanghaiTech University Research Ethics Committee has approved the proposed project below based on the information provided in the proposal.