Epstein-Barr virus suppresses N6-methyladenosine modification of TLR9 to promote immune evasion

作者：Xiaoyue Zhang, Zhengshuo Li, Peng Qiu, Can Liu, Yangge Wu, Yuqing Wen, Run Zheng, Chenxiao Xu, Junrui Tian, Xiang Zheng, Qun Yan, Jia Wang, Jian Ma · 发表于：Journal of Biological Chemistry · 年份：2024 · DOI：10.1016/j.jbc.2024.107226 · 被引用次数：29 · 研究领域：Cytomegalovirus and herpesvirus research、RNA modifications and cancer、Viral-associated cancers and disorders

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 6 -methyladenosine (m 6 A) 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) m 6 A modification levels and thus inhibits TLR9 expression. TLR9 has multiple m 6 A modification sites. Knockdown of METTL3, an m 6 A "writer", decreases TLR9 protein expression by inhibiting its mRNA stability. Mechanistically, Epstein-Barr nuclear antigen 1 (EBNA1) increases METTL3 protein degradation via K48-linked ubiquitin-proteasome pathway. Additionally, YTHDF1 was identified as an m 6 A "reader" of TLR9, enhancing TLR9 expression by promoting mRNA translation in an m 6 A -dependent manner, which suggests that EBV inhibits TLR9 translation by "hijacking" host m 6 A modification mechanism. Using the METTL3 inhibitor STM2457 inhibits TLR9-induced B cell proliferation and Ig 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 m 6 A modification system.