Epstein-Barr virus (EBV) is a human tumor virus associated with a variety of malignancies, including nasopharyngeal carcinoma, gastric cancers, and B-cell lymphomas. N-methyladenosine (mA) modifications modulate a wide range of cellular processes and participate in the regulation of virus-host cell interactions. Here, we discovered that EBV infection downregulates toll-like receptor 9 (TLR9) mA modification levels and thus inhibits TLR9 expression. TLR9 has multiple mA modification sites. Knockdown of METTL3, an mA “writer”, decreases TLR9 protein expression by inhibiting its mRNA stability. Mechanistically, Epstein-Barr nuclear antigen 1 increases METTL3 protein degradation K48-linked ubiquitin-proteasome pathway. Additionally, YTHDF1 was identified as an mA “reader” of TLR9, enhancing TLR9 expression by promoting mRNA translation in an mA -dependent manner, which suggests that EBV inhibits TLR9 translation by “hijacking” host mA modification mechanism. Using the METTL3 inhibitor STM2457 inhibits TLR9-induced B cell proliferation and immunoglobulin secretion, and opposes TLR9-induced immune responses to assist tumor cell immune escape. In clinical lymphoma samples, the expression of METTL3, YTHDF1, and TLR9 was highly correlated with immune cells infiltration. This study reveals a novel mechanism that EBV represses the important innate immunity molecule TLR9 through modulating the host mA modification system.

中文翻译：

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Epstein-Barr病毒抑制TLR9的N6-甲基腺苷修饰以促进免疫逃避

EB 病毒 (EBV) 是一种与多种恶性肿瘤相关的人类肿瘤病毒，包括鼻咽癌、胃癌和 B 细胞淋巴瘤。 N-甲基腺苷 (mA) 修饰可调节多种细胞过程并参与病毒与宿主细胞相互作用的调节。在这里，我们发现 EBV 感染下调 Toll 样受体 9 (TLR9​​) mA 修饰水平，从而抑制 TLR9 表达。 TLR9有多个mA修饰位点。 METTL3（一种 mA“写入器”）的敲除可通过抑制其 mRNA 稳定性来降低 TLR9 蛋白的表达。从机制上讲，Epstein-Barr 核抗原 1 会增加 METTL3 蛋白降解 K48 连接的泛素蛋白酶体途径。此外，YTHDF1被鉴定为TLR9的m6A“阅读器”，通过以m6A依赖性方式促进mRNA翻译来增强TLR9表达，这表明EBV通过“劫持”宿主m6A修饰机制来抑制TLR9翻译。利用METTL3抑制剂STM2457抑制TLR9诱导的B细胞增殖和免疫球蛋白分泌，并对抗TLR9诱导的免疫反应，协助肿瘤细胞免疫逃逸。在临床淋巴瘤样本中，METTL3、YTHDF1和TLR9的表达与免疫细胞浸润高度相关。这项研究揭示了EBV通过调节宿主m6A修饰系统来抑制重要的先天免疫分子TLR9的新机制。