PRRSV Nsp12 targets PSMA2 to suppress host proteasome activity and promote viral survival

Porcine reproductive and respiratory syndrome virus (PRRSV) poses a significant threat to the global swine industry, employing complex mechanisms to interact with the host and evade host immune responses. The ubiquitin-proteasome system (UPS) is central to host antiviral innate immunity, yet its interplay with PRRSV remains poorly understood. In this study, Proteasome 20S Subunit Alpha 2 (PSMA2) was identified as a novel host restriction factor against highly pathogenic PRRSV (HP-PRRSV). Through overexpression and siRNA knockdown experiments, it was demonstrated that PSMA2 effectively inhibits PRRSV replication in a time- and dose-dependent manner, exerting antiviral effects during the mid-to-late post-entry stages of replication. Mechanistically, PSMA2 overexpression enhances overall cellular proteasome activity and specifically upregulates transcription of immunoproteasome activator subunits PSME1, PSME2, and PSME3. As a countermeasure, the PRRSV JXA1 strain induces the degradation of PSMA2 protein via the autophagy pathway, a process contingent on active viral replication. Further screening identified PRRSV nonstructural protein 12 (Nsp12) as a viral factor associated with the autophagy-dependent reduction of PSMA2. In parallel, PRRSV infection suppresses global proteasome activity, indicating that the virus adopts a two-pronged strategy to undermine this host defense pathway. These findings demonstrate that PRRSV hijacks autophagy machinery to eliminate a key proteasome-associated restriction factor. Collectively, our results highlight the intricate interplay between PRRSV and the host proteasome system and provide novel insights into viral pathogenesis.