Department of Cell and Chemical Biology, Leiden University Medical Center (LUMC), Leiden, the Netherlands; Oncode Institute, Leiden University Medical Center (LUMC), Leiden, the Netherlands.
Department of Cell and Chemical Biology, Leiden University Medical Center (LUMC), Leiden, the Netherlands.
J Biol Chem. 2024 Sep;300(9):107645. doi: 10.1016/j.jbc.2024.107645. Epub 2024 Aug 8.
Epstein-Barr virus (EBV), the causative agent of infectious mononucleosis, persistently infects over 90% of the human adult population and is associated with several human cancers. To establish life-long infection, EBV tampers with the induction of type I interferon (IFN I)-dependent antiviral immunity in the host. How various EBV genes help orchestrate this crucial strategy is incompletely defined. Here, we reveal a mechanism by which the EBV nuclear antigen 3A (EBNA3A) may inhibit IFNβ induction. Using proximity biotinylation we identify the histone acetyltransferase P300, a member of the IFNβ transcriptional complex, as a binding partner of EBNA3A. We further show that EBNA3A also interacts with the activated IFN-inducing transcription factor interferon regulatory factor 3 that collaborates with P300 in the nucleus. Both events are mediated by the N-terminal domain of EBNA3A. We propose that EBNA3A limits the binding of interferon regulatory factor 3 to the IFNβ promoter, thereby hampering downstream IFN I signaling. Collectively, our findings suggest a new mechanism of immune evasion by EBV, affected by its latency gene EBNA3A.
EB 病毒（EBV）是传染性单核细胞增多症的病原体，持续感染超过 90%的成年人口，并与几种人类癌症有关。为了建立终身感染，EBV 篡改了宿主中 I 型干扰素（IFN I）依赖性抗病毒免疫的诱导。各种 EBV 基因如何帮助协调这一关键策略尚未完全确定。在这里，我们揭示了 EBV 核抗原 3A（EBNA3A）可能抑制 IFNβ诱导的机制。使用邻近生物素化，我们确定了组蛋白乙酰转移酶 P300 作为 EBNA3A 的结合伴侣，它是 IFNβ 转录复合物的成员。我们进一步表明，EBNA3A 还与激活的 IFN 诱导转录因子干扰素调节因子 3 相互作用，该因子与 P300 在核内协作。这两个事件均由 EBNA3A 的 N 端结构域介导。我们提出，EBNA3A 限制了干扰素调节因子 3 与 IFNβ 启动子的结合，从而阻碍了下游 IFN I 信号转导。总之，我们的研究结果表明，EBV 通过其潜伏基因 EBNA3A 逃避免疫的新机制。
