Grass carp pyruvate kinase PKM acts as a key viral helper by orchestrating NS80-mediated VIB formation and multifaceted inhibition of the RLR-IFN-STAT1 antiviral cascade.

Abstract

Grass carp reovirus (GCRV) causes devastating disease in grass carp, posing a severe threat to aquaculture sustainability. The RLR-IFN-STAT pathway serves as the core of host antiviral defense, yet the mechanisms by which GCRV subverts this cascade remain poorly understood. Here, we investigated the role of grass carp PKM (gcPKM) in GCRV infection and identified its dual pro-viral mechanisms. gcPKM promotes GCRV replication by localizing to viral inclusion bodies (VIBs) and interacting with GCRV NS80 to enhance VIB biogenesis. Meanwhile, it disrupts the RLR-IFN-STAT cascade at multiple nodes: degrading core RLR components including RIG-I, MAVS, TBK1, IRF3 and IRF7 without direct interaction to inhibit IFN production, physically interacting with gcSTAT1a to induce its cytoplasmic sequestration and drive gcSTAT1a degradation through a lysosome-dependent, non-canonical autophagic pathway, thereby antagonizing gcSTAT1a's antiviral function. This study uncovers novel insights into gcPKM's multifaceted role in GCRV pathogenesis, highlighting it as a key viral helper that targets both VIB formation and antiviral signaling, and provides a potential target for developing anti-GCRV strategies in aquaculture.