FTO controls CD8+ T cell survival and effector response by modulating m6A methylation of Fas

作者：Lina Sun, Tianzhe Zhang, Ge Yao, Zhihong Yao, Yanhong Su, Qianhao Wang, Yang Chen, Boxiao He, Renyi Ding, Cangang Zhang, Linbo Lan, Ruonan Liu, Huanxin Ping, Dan Zhang, Lin Shi, Xiaobo Zhou, Xiaoxuan Jia, Chenming Sun, Lingli Liang, Lianjun Zhang, Baojun Zhang · 发表于：Cell Death and Disease · 年份：2025 · DOI：10.1038/s41419-025-07606-z · 被引用次数：10 · 研究领域：RNA modifications and cancer、Cancer-related gene regulation、HVDC Systems and Fault Protection

Abstract Functional CD8 + T cell immunity is essential for immune surveillance and host defense against infection and tumors. Epigenetic mechanisms, particularly RNA modification, in controlling CD8 + T cell immune response is not fully elucidated. Here, by T cell-specific deletion of fat mass and obesity-associated protein (FTO), a critical N6-methyladenosine (m 6 A) demethylase, we revealed that FTO was indispensable for adequate CD8 + T cell immune response and protective function. FTO ablation led to considerable cell death in activated CD8 + T cells, which was attributed to cell apoptosis. MeRIP-seq analysis revealed an increase in m 6 A methylation on Fas mRNA in FTO-deficient CD8 + T cells. The loss of FTO promoted Fas expression via enhancing the Fas mRNA stability, which depended on the m 6 A reader insulin-like growth factor-2 mRNA-biding proteins 3 (IGF2BP3). Mutation of the Fas m 6 A sites or knockdown IGF2BP3 could normalize the upregulated Fas expression and apoptosis levels caused by FTO ablation in CD8 + T cells. Our findings delineate a novel epigenetic regulatory mechanism of FTO-mediated m 6 A modification in supporting CD8 + T cell survival and effector responses, providing new insights into understanding the post-transcriptional regulation in CD8 + T cell immunological functions and the potential therapeutic intervention.