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

• Published in: The Journal of biological chemistry Vol. 300; no. 5; p. 107226
• Main Authors: Zhang, Xiaoyue, Li, Zhengshuo, Peng, Qiu, Liu, Can, Wu, Yangge, Wen, Yuqing, Zheng, Run, Xu, Chenxiao, Tian, Junrui, Zheng, Xiang, Yan, Qun, Wang, Jia, Ma, Jian
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.05.2024; American Society for Biochemistry and Molecular Biology
• Subjects: Epstein-Barr virus; immune evasion; m6A modification; METTL3; TLR9; m6A modification; TNF; IFN; CHX; FBS; pDCs; EBV; ODN; Epstein-Barr virus; TLR; HBV; RT-qPCR; gDNA; MOI; METTL3; IP; CFSE; MeRIP; PBMCs; EBNA; immune evasion; TLR9; RIP; m6A; Ig
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/j.jbc.2024.107226

Epstein-Barr virus (EBV) is a human tumor virus associated with a variety of malignancies, including nasopharyngeal carcinoma, gastric cancers, and B-cell lymphomas. N6-methyladenosine (m6A) 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) m6A modification levels and thus inhibits TLR9 expression. TLR9 has multiple m6A modification sites. Knockdown of METTL3, an m6A “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 m6A “reader” of TLR9, enhancing TLR9 expression by promoting mRNA translation in an m6A -dependent manner, which suggests that EBV inhibits TLR9 translation by “hijacking” host m6A 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 m6A modification system.