Porcine deltacoronavirus nucleocapsid protein inhibits RIG-I signaling pathway by suppressing G3BP1-mediated stress granules formation.

Porcine deltacoronavirus (PDCoV) is an emerging zoonotic pathogen causing severe diarrhea in suckling piglets. Stress granules (SGs), stress-induced cytoplasmic condensates, are pivotal to the antiviral innate immune response. However, the interaction between PDCoV and SGs remains unclear. Here, we found that PDCoV triggered the formation of SGs during early infection, but these structures gradually disassembled in the late stage, while exogenously induced SGs significantly inhibited PDCoV replication. Mechanistically, we identified the nucleocapsid (N) protein as a potent SGs antagonist. The N protein can interact with Ras-GTPase-activating protein SH3-domain-binding protein 1 (G3BP1, the core component of SGs), thereby disrupting SGs assembly. Furthermore, we found that G3BP1 promotes type I interferon (IFN-I) production by recruiting retinoic acid-inducible gene-I (RIG-I). The PDCoV N protein competitively blocks this G3BP1-RIG-I interaction, leading to impaired IFN-I signaling. In addition, we found that this SGs-inhibitory function is conserved across diverse coronaviruses and correlates with structural conservation of N proteins. Our findings reveal a novel and conserved immune evasion mechanism in which coronaviruses antagonize the SGs-mediated antiviral pathway via their N proteins to promote replication. Importantly, this mechanism is structurally conserved across diverse coronaviruses, thereby identifying the N protein as a promising target for broad-spectrum antiviral development.