Epstein-Barr Virus Envelope Glycoprotein gp110 Inhibits IKKi-Mediated Activation of NF-κB and Promotes the Degradation of ß-Catenin.

Epstein-Barr virus (EBV) infects host cells and establishes a latent infection that requires evasion of host innate immunity. A variety of EBV-encoded proteins that manipulate the innate immune system have been reported, but whether other EBV proteins participate in this process is unclear. EBV-encoded envelope glycoprotein gp110 is a late protein involved in virus entry into target cells and enhancement of infectivity. Here, we reported that gp110 inhibits RIG-I-like receptor pathway-mediated promoter activity of interferon-ß (IFN-ß) as well as the transcription of downstream antiviral genes to promote viral proliferation. Mechanistically, gp110 interacts with the inhibitor of NF-κB kinase (IKKi) and restrains its K63-linked polyubiquitination, leading to attenuation of IKKi-mediated activation of NF-κB and repression of the phosphorylation and nuclear translocation of p65. Additionally, gp110 interacts with an important regulator of the Wnt signaling pathway, ß-catenin, and induces its K48-linked polyubiquitination degradation via the proteasome system, resulting in the suppression of ß-catenin-mediated IFN-ß production. Taken together, these results suggest that gp110 is a negative regulator of antiviral immunity, revealing a novel mechanism of EBV immune evasion during lytic infection. IMPORTANCE Epstein-Barr virus (EBV) is a ubiquitous pathogen that infects almost all human beings, and the persistence of EBV in the host is largely due to immune escape mediated by its encoded products. Thus, elucidation of EBV's immune escape mechanisms will provide a new direction for the design of novel antiviral strategies and vaccine development. Here, we report that EBV-encoded gp110 serves as a novel viral immune evasion factor, which inhibits RIG-I-like receptor pathway-mediated interferon-ß (IFN-ß) production. Furthermore, we found that gp110 targeted two key proteins, inhibitor of NF-κB kinase (IKKi) and ß-catenin, which mediate antiviral activity and the production of IFN-ß. gp110 inhibited K63-linked polyubiquitination of IKKi and induced ß-catenin degradation via the proteasome, resulting in decreased IFN-ß production. In summary, our data provide new insights into the EBV-mediated immune evasion surveillance strategy.

Epstein-Barr virus envelope glycoprotein 110 inhibits NF-κB activation by interacting with NF-κB subunit p65.

Epstein-Barr virus (EBV) is a member of the lymphotropic virus family and is highly correlated with some human malignant tumors. It has been reported that envelope glycoprotein 110 (gp110) plays an essential role in viral fusion, DNA replication, and nucleocapsid assembly of EBV. However, it has not been established whether gp110 is involved in regulating the host's innate immunity. In this study, we found that gp110 inhibits tumor necrosis factor α-mediated NF- κB promoter activity and the downstream production of NF- κB-regulated cytokines under physiological conditions. Using dual-luciferase reporter assays, we showed that gp110 might impede the NF-κB promoter activation downstream of NF-κB transactivational subunit p65. Subsequently, we used coimmunoprecipitation assays to demonstrate that gp110 interacts with p65 during EBV lytic infection, and that the C-terminal cytoplasmic region of gp110 is the key interaction domain with p65. Furthermore, we determined that gp110 can bind to the N-terminal Rel homologous and C-terminal domains of p65. Alternatively, gp110 might not disturb the association of p65 with nontransactivational subunit p50, but we showed it restrains activational phosphorylation (at Ser536) and nuclear translocation of p65, which we also found to be executed by the C-terminal cytoplasmic region of gp110. Altogether, these data suggest that the surface protein gp110 may be a vital component for EBV to antagonize the host's innate immune response, which is also helpful for revealing the infectivity and pathogenesis of EBV.