HSPA5 induces autophagy targeting VP2 through the PERK-eIF2α signaling pathway to inhibit SVA replication

ABSTRACT Senecavirus A (SVA), also known as Seneca Valley virus (SVV), is an important small RNA virus that causes swine vesicular disease, posing a significant threat to the global swine industry. To date, the molecular mechanism of SVA replication remains poorly understood. Heat shock proteins (HSPs) are a family of molecular chaperone proteins that are widely present in organisms. More and more studies have shown that HSPs are associated with viral infections. Here, we screened HSPs and found that overexpression of HSPA5 significantly inhibited SVA replication, while knockout of HSPA5 promoted SVA proliferation. Further analysis showed that HSPA5 started to inhibit SVA proliferation at the stage of viral replication, and by screening SVA-encoded proteins, we found that HSPA5 degraded and interacted with the viral protein VP2 through the autophagy pathway. Mechanistically, HSPA5 participates in the degradation of VP2 proteins by activating autophagy mediated by the PERK-eIF2α pathway. In addition, the NBD region of HSPA5 is critical for VP2 degradation, and the Thr180 residue of VP2 has been identified as a key target for HSPA5 to inhibit the VP2 protein. The VP2 mutant virus rT180N showed resistance to the antiviral activity of HSPA5 compared with wild-type SVA and repair virus rT180N(R). In conclusion, these findings indicate that HSPA5 is an effective antiviral factor that suppresses SVA infection and contributes to a better understanding of the antiviral mechanism of HSPA5 and virus-host interactions. IMPORTANCE Senecavirus A (SVA) infections have been reported in many pork-producing countries, but the lack of a commercial vaccine has caused significant economic losses to the world pig industry. In this study, we determined the antiviral role of HSPA5 in SVA and found that HSPA5 induces autophagy targeting VP2 through the PERK-eIF2α signaling pathway to inhibit SVA replication. In addition, the NBD region of HSPA5 is essential for the degradation of the VP2 protein, and HSPA5 targets the threonine residue at position 180 of the VP2 protein to exert its degradative function. These findings broaden the antiviral spectrum of SVA and provide a better understanding of the antiviral mechanism of SVA and virus-host interactions, providing important clues for the development of effective vaccines.