Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China; Cancer Research Institute, School of Basic Medical Science, Central South University, Changsha, Hunan, China; NHC Key Laboratory of Carcinogenesis, Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Hunan Key Laboratory of Cancer Metabolism, Changsha, Hunan, China.
Department of Pathology, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China.
J Biol Chem. 2024 May;300(5):107226. doi: 10.1016/j.jbc.2024.107226. Epub 2024 Mar 25.
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 via 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.
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。N6-甲基腺苷（m6A）修饰调节广泛的细胞过程，并参与病毒-宿主细胞相互作用的调节。在这里，我们发现 EBV 感染下调了 Toll 样受体 9（TLR9）的 m6A 修饰水平，从而抑制了 TLR9 的表达。TLR9 有多个 m6A 修饰位点。mA“写作者”METTL3 的敲低通过抑制其 mRNA 稳定性降低 TLR9 蛋白表达。在机制上，EBV 核抗原 1 通过 K48 连接的泛素-蛋白酶体途径增加 METTL3 蛋白降解。此外，YTHDF1 被鉴定为 TLR9 的 m6A“读取器”，通过促进 mA 依赖性 mRNA 翻译来增强 TLR9 表达，这表明 EBV 通过“劫持”宿主 m6A 修饰机制抑制 TLR9 翻译。使用 METTL3 抑制剂 STM2457 抑制 TLR9 诱导的 B 细胞增殖和免疫球蛋白分泌，并反对 TLR9 诱导的免疫反应，以协助肿瘤细胞免疫逃避。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。
