Engagement of the G3BP2-TRIM25 Interaction by Nucleocapsid Protein Suppresses the Type I Interferon Response in SARS-CoV-2-Infected Cells

The nucleocapsid (N) protein contributes to key steps of the SARS-CoV-2 life cycle, including packaging of the virus genome and modulating interactions with cytoplasmic components. Expanding knowledge of the N protein acting on cellular proteins and interfering with innate immunity is critical for studying the host antiviral strategy. In the study on SARS-CoV-2 infecting human bronchial epithelial cell line s1(16HBE), we identified that the N protein can promote the interaction between GTPase-activating protein SH3 domain–binding protein 2 (G3BP2) and tripartite motif containing 25 (TRIM25), which is involved in formation of the TRIM25-G3BP2-N protein interactome. Our findings suggest that the N protein is enrolled in the inhibition of type I interferon production in the process of infection. Meanwhile, upgraded binding of G3BP2 and TRIM25 interferes with the RIG-I-like receptor signaling pathway, which may contribute to SARS-CoV-2 escaping from cellular innate immune surveillance. The N protein plays a critical role in SARS-CoV-2 replication. Our study suggests that the N protein and its interacting cellular components has potential for use in antiviral therapy, and adding N protein into the vaccine as an antigen may be a good strategy to improve the effectiveness and safety of the vaccine. Its interference with innate immunity should be strongly considered as a target for SARS-CoV-2 infection control and vaccine design.