BSRF1 modulates IFN-β-mediated antiviral responses by inhibiting NF-κB activity via an IKK-dependent mechanism in Epstein-Barr virus infection.

The Epstein-Barr virus (EBV) encoded tegument protein BSRF1 plays a significant role in the processes of viral maturation and release, however, it's not clear whether BSRF1 is involved in the modulation of host innate immunity. In this study, we demonstrated that BSRF1 can inhibit interferon β (IFN-β) production by downregulating nuclear factor kappa B (NF-κB) activity and subsequently reducing the yield of inflammatory cytokines, thereby facilitating viral replication. Dual luciferase reporter assays indicated that BSRF1 may inhibit NF-κB signaling at the level of IKK or between IKK and p65, while co-immunoprecipitation experiments revealed its association with multiple critical host adaptor proteins. Mechanistically, BSRF1 hinders the phosphorylation of IκBα at Ser32/36 and K48-linked polyubiquitination, thereby preventing proteasome-mediated degradation of IκBα by disrupting the assembly of the regulatory subunits within the IKK complex. Although BSRF1 interacts with p65 and its N-terminal domain, it does not alter the formation of the p65/p50 heterodimer. Instead, it prevents the nuclear translocation of p65 by inhibiting the dissociation of IκBα from the NF-κB dimer. Collectively, these findings suggested that BSRF1 assists EBV's evasion of host innate immune system by inhibiting the antiviral response to IFN-β through the NF-κB signaling pathway, potentially contributing to the virus's ability to establish persistent infection and its association with tumorigenesis.