EBV encoded tegument protein BKRF4 suppresses RLR signaling pathway-mediated interferon production through inhibiting the activation of IRF3 and IRF7

Epstein-Barr virus (EBV), a member of gamma herpesvirus subfamily, infects more than 90% of the people in the world. There are some studies on EBV-mediated regulation of type I interferon (IFN-I) signaling, however, the underlying mechanism is still not fully understood. In this study, we demonstrated that the EBV encoded tegument protein BKRF4 could suppress RIG-I-like receptor (RLR) signaling pathway-induced IFN-β promoter activity and the mRNA transcription of IFN-β and downstream IFN-stimulated genes, which is favorable for RNA and DNA viral replications. Mechanically, BKRF4 was shown to interact with IRF3 and restrain its phosphorylation, dimerization, and nuclear translocation. Specifically, aa71-95 of BKRF4 was essential for its association with IRF3 and the inhibition of IFN-β promoter activity. Moreover, BKRF4 also could interplay with activated IRF7 but didn't affect the formation of IRF7 homodimer or IRF3/IRF7 heterodimer, yet it could impede the nuclear accumulation of IRF7. In addition, knockdown of BKRF4 during EBV lytic replication significantly enhanced IFN-β promoter activity and the phosphorylation and dimerization of IRF3. Taken together, our findings suggested that BKRF4 could negatively regulate the RLR-mediated IFN-β antiviral signaling, which provides new evidence for the molecular mechanism exploited by EBV to evade the host innate immunity.