MARCH8 inhibits PRRSV-2 replication by targeting viral GP5 for proteasomal degradation at a conserved lysine 163.

Porcine reproductive and respiratory syndrome virus (PRRSV) continues to pose a significant threat to global swine production. In China, PRRSV type 2 (PRRSV-2) is the predominant strain, and the inadequate cross-protection provided by existing vaccines highlights the urgent need for novel antiviral agents capable of effectively controlling PRRSV-2 infections. The host membrane-associated RING-CH 8 protein (MARCH8) has been demonstrated to play diverse roles in viral replication, either facilitating or inhibiting various viruses. However, its specific function in PRRSV infection and its broader role within the arterivirus family remain poorly understood. In this study, we identify MARCH8 as a potent inhibitor of PRRSV replication. Mechanically, we discovered that MARCH8 interacts with the viral glycoprotein GP5, which is crucial for PRRSV replication. Specifically, MARCH8 binds to GP5 and promotes its Lys-163-linked K48 polyubiquitination, subsequently targeting it for proteasomal degradation. Our findings reveal a novel antiviral mechanism through which MARCH8 restricts PRRSV replication and provide insights into virus-host interactions that may inform the development of new antiviral strategies.