OXCT1‐driven succinylation of PSMG3 stabilizes the proteasome to facilitate picornavirus replication

Abstract Foot‐and‐mouth disease virus (FMDV) rapidly replicates and spreads in porcine tonsils and the submaxillary lymph nodes, yet the host response in these immune tissues remains unclear. Here, we performed integrated multi‐omics analyses to systematically characterize host responses during FMDV infection. We found that FMDV induces extensive metabolic reprogramming accompanied by global remodeling of protein post‐translational modifications, which retunes the metabolic, immune, transcriptional, translational, and signal transduction biological processes. Of these, lysine succinylation is prominently upregulated. Mechanistically, FMDV increases intracellular succinyl‐CoA levels and promotes the succinylation of the proteasome assembly chaperone PSMG3 at lysine 104. This modification is associated with the stability of the PSMG3‐PSMG4 complex and proteasome function, supporting viral propagation. Further investigation revealed that FMDV‐upregulated 3‐oxoacid CoA‐transferase 1 (OXCT1) associates with PSMG3 succinylation. Notably, the succinylation of PSMG3 also significantly supports the replication of other picornaviruses, including enterovirus 71 and Seneca Valley virus. Pharmacological inhibition of PSMG3 succinylation suppresses picornavirus replication in vivo and in vitro. Collectively, our findings reveal that host metabolism is linked to proteostasis and picornavirus infection, facilitating the development of new vaccines and antivirals and advancing our understanding of FMDV pathogenesis.