EBV latent nuclear antigen EBNA3A modulates IRF3-dependent IFNβ expression

Epstein-Barr virus (EBV) persistently infects over 90% of the human population and is the causative agent of infectious mononucleosis and human cancers. For the establishment of life-long infection, EBV tampers with the induction of type I interferon (IFN I)-dependent antiviral immunity in the host. How various EBV latency genes help orchestrate this crucial strategy is incompletely defined. Here, we reveal the mechanism by which the EBV nuclear antigen 3A (EBNA3A) inhibits IFNβ induction. Using proximity biotinylation we identify the histone acetyltransferase P300, a member of the IFNβ transcription complex, as a binding partner of EBNA3A. Follow-up experiments further demonstrate that EBNA3A also interacts with the activated IFN-inducing transcription factor IRF3 that collaborates with P300 in the nucleus and both events are mediated by the N-terminal domain of EBNA3A. Mechanistic studies reveal that EBNA3A reduces the binding of IRF3 to the IFNβ promotor, thereby hampering downstream IFN I signaling. These results reveal a novel mechanism by which viral immune evasion takes place.