The PCK2-Traf6-Tollip Axis Restricts PEDV Replication by Orchestrating Selective Autophagic Degradation of the Viral Nucleocapsid Protein.

Porcine epidemic diarrhea virus (PEDV) is a devastating enteric pathogen in neonatal piglets, causing outbreaks with high mortality. The lack of effective vaccines or treatments makes elucidating host-pathogen interactions essential for developing control strategies. In this study, we identify phosphoenolpyruvate carboxykinase 2 (PCK2) as a host restriction factor that targets the viral nucleocapsid (N) protein for degradation, thereby suppressing PEDV replication. This PCK2-mediated antiviral effect was reversed by autophagy inhibitors, indicating the involvement of a selective autophagic. Mechanistically, we found that PCK2, the N protein, the E3 ubiquitin ligase Traf6, and the cargo receptor Tollip form a functional complex. Depletion of either Traf6 or Tollip disrupted the autophagy pathway, restored N protein stability, and consequently rescued viral replication from PCK2 inhibition. This study unveils a novel antiviral mechanism in which PCK2 orchestrates the selective autophagic degradation of the PEDV N protein, highlighting the PCK2-Traf6-Tollip axis as a promising therapeutic direction.