DPV UL46 activates EGFR-PI3K-AKT pathway to antagonize innate immunity by interfering with cGAS-STING-TBK-IRF7 Signalsome formation.

Duck plague virus (DPV), a representative species of the Alphaherpesvirinae subfamily, poses significant economic and biosecurity threats to poultry production. Although the EGFR-PI3K-AKT signaling pathway is known to regulate diverse cellular processes-including cell growth, protein synthesis and immune regulation-and plays a significant role in viral infections, its interplay with the cGAS-STING pathway during DPV infection remains unclear. In this study, we demonstrate that DPV infection induces AKT1 phosphorylation in duck embryo fibroblast (DEF) cells. Overexpression of AKT1 significantly suppressed cGAS-STING-mediated production of IFN-β and ISGs, whereas pharmacological inhibition of AKT1 with GSK-690693 enhanced these responses. Mechanistically, AKT1 suppresses innate immune signaling by targeting multiple components of the cGAS-STING-TBK1-IRF7 axis and interfering with critical protein-protein interactions within this complex in a kinase-dependent manner. We identified DPV UL46 as a key viral effector that activates AKT1 phosphorylation via EGFR and PI3K. Treatment with inhibitors of EGFR (gefitinib), PI3K (LY294002), or AKT (GSK-690693) effectively blocked DPV-induced AKT1-Ser473 phosphorylation, weaken the inhibitory effect of DPV on cGAS+STING induced innate immunity and consequently suppressed viral replication in DEF cells. These findings provide the first evidence of a molecular mechanism by which DPV utilizes UL46 to hijack the EGFR-PI3K-AKT pathway, thereby interfering with the cGAS-STING-TBK1-IRF7 signalsome to evade host antiviral defenses. Our study provides novel mechanistic insights into DPV pathogenesis and identifies promising targets for antiviral intervention.