PRRSV nucleocapsid protein suppresses pyroptosis by recruiting OTUD4 to degrade caspase-1

Porcine reproductive and respiratory syndrome virus (PRRSV) employs complex strategies to evade host immunity, yet its interplay with the pyroptotic cell death pathway remains unclear. While Caspase-1/gasdermin D(GSDMD) -mediated pyroptosis is a crucial antiviral defense, we demonstrate that Caspase-1 exerts antiviral activity against PRRSV, whereas the Caspase-1 inhibitor VX765 promotes viral replication. In response, the PRRSV nucleocapsid protein (N) inhibits pyroptosis by driving Caspase-1 degradation. Mechanistically, PRRSV-N recruits OTU deubiquitinase 4 (OTUD4) and binds Caspase-1, a process in which the PRRSV-N-terminal domain (residues 1–57) plays a crucial role. This interaction promotes the removal of K63-linked ubiquitination from Caspase-1, triggering its proteasomal degradation. Notably, the OTUD4 catalytic mutant (C45A) also destabilized Caspase-1, revealing that OTUD4 acts in a catalytic-independent regulatory role in this context. Thus, PRRSV-N exploits OTUD4 to evade pyroptosis through a novel mechanism, highlighting the PRRSV-N-OTUD4 axis as a promising therapeutic target.