Pseudorabies virus EP0 protein targets cGAS and STING for degradation through autophagy.

The cGAS-STING axis is a central DNA-sensing pathway that initiates antiviral immune responses, yet the mechanisms by which viruses evade this defense system remain incompletely understood. Here, we identify the early protein EP0 of pseudorabies virus (PRV), a member of the Alphaherpesvirinae subfamily, as a viral virulence factor. Mechanistically, PRV EP0 suppresses cGAS-STING-mediated innate immunity by promoting the degradation of both cGAS and STING via the autophagy-lysosome pathway, thereby inhibiting downstream phosphorylation of TBK1 and IRF3. This degradation is strictly dependent on the structural integrity of EP0's functional domains. Notably, deletion of cGAS or STING significantly enhances replication of EP0-deficient PRV. Together, these findings establish PRV EP0 as a key antagonist of cGAS-STING-mediated innate immunity, offering insights that may inform the development of more effective vaccines and antiviral therapies.