Department of Laboratory Medicine, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, Guangzhou Medical University, Qingyuan, China.
Department of Clinical Laboratory, Fifth Affiliated Hospital, Southern Medical University, Guangzhou, China.
Microbiol Spectr. 2023 Jun 15;11(3):e0032623. doi: 10.1128/spectrum.00326-23. Epub 2023 Apr 6.
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-β (IFN-β) 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, β-catenin, and induces its K48-linked polyubiquitination degradation via the proteasome system, resulting in the suppression of β-catenin-mediated IFN-β 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. 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-β (IFN-β) production. Furthermore, we found that gp110 targeted two key proteins, inhibitor of NF-κB kinase (IKKi) and β-catenin, which mediate antiviral activity and the production of IFN-β. gp110 inhibited K63-linked polyubiquitination of IKKi and induced β-catenin degradation via the proteasome, resulting in decreased IFN-β production. In summary, our data provide new insights into the EBV-mediated immune evasion surveillance strategy.
EBV 病毒（EBV）感染宿主细胞并建立潜伏感染，需要逃避宿主先天免疫。已经报道了多种 EBV 编码蛋白可操纵先天免疫系统，但其他 EBV 蛋白是否参与这一过程尚不清楚。EBV 编码的包膜糖蛋白 gp110 是一种晚期蛋白，参与病毒进入靶细胞并增强感染性。在这里，我们报道 gp110 抑制 RIG-I 样受体途径介导的干扰素-β（IFN-β）启动子活性以及下游抗病毒基因的转录，从而促进病毒增殖。在机制上，gp110 与 NF-κB 激酶（IKKi）的抑制剂相互作用，并抑制其 K63 连接的多泛素化，导致 IKKi 介导的 NF-κB 激活减弱和 p65 的磷酸化和核转位受到抑制。此外，gp110 与 Wnt 信号通路的一个重要调节剂β-catenin 相互作用，并通过蛋白酶体系统诱导其 K48 连接的多泛素化降解，从而抑制β-catenin 介导的 IFN-β产生。总之，这些结果表明 gp110 是抗病毒免疫的负调节剂，揭示了 EBV 在裂解感染期间免疫逃避的新机制。 Epstein-Barr 病毒（EBV）是一种普遍存在的病原体，几乎感染所有人类，EBV 在宿主中的持续存在在很大程度上是由于其编码产物介导的免疫逃避。因此，阐明 EBV 的免疫逃避机制将为设计新型抗病毒策略和疫苗开发提供新的方向。在这里，我们报告 EBV 编码的 gp110 是一种新型病毒免疫逃避因子，可抑制 RIG-I 样受体途径介导的干扰素-β（IFN-β）产生。此外，我们发现 gp110 靶向两个关键蛋白，即 NF-κB 激酶（IKKi）抑制剂和 β-catenin，它们介导抗病毒活性和 IFN-β 的产生。gp110 抑制 IKKi 的 K63 连接多泛素化并通过蛋白酶体诱导 β-catenin 降解，导致 IFN-β 产生减少。总之，我们的数据为 EBV 介导的免疫逃避监测策略提供了新的见解。
