FTO controls CD8+ T cell survival and effector response by modulating m6A methylation of Fas
Functional CD8<sup>+</sup> T cell immunity is essential for immune surveillance and host defense against infection and tumors. Epigenetic mechanisms, particularly RNA modification, in controlling CD8<sup>+</sup> 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<sup>6</sup>A) demethylase, we revealed that FTO was indispensable for adequate CD8<sup>+</sup> T cell immune response and protective function. FTO ablation led to considerable cell death in activated CD8<sup>+</sup> T cells, which was attributed to cell apoptosis. MeRIP-seq analysis revealed an increase in m<sup>6</sup>A methylation on Fas mRNA in FTO-deficient CD8<sup>+</sup> T cells. The loss of FTO promoted Fas expression via enhancing the Fas mRNA stability, which depended on the m<sup>6</sup>A reader insulin-like growth factor-2 mRNA-biding proteins 3 (IGF2BP3). Mutation of the Fas m<sup>6</sup>A sites or knockdown IGF2BP3 could normalize the upregulated Fas expression and apoptosis levels caused by FTO ablation in CD8<sup>+</sup> T cells. Our findings delineate a novel epigenetic regulatory mechanism of FTO-mediated m<sup>6</sup>A modification in supporting CD8<sup>+</sup> T cell survival and effector responses, providing new insights into understanding the post-transcriptional regulation in CD8<sup>+</sup> T cell immunological functions and the potential therapeutic intervention.
Authors
- Chen Yang (ORCID: https://orcid.org/0000-0003-4619-2469)
- Xiaoxuan Jia
- Cangang Zhang (ORCID: https://orcid.org/0000-0001-6443-7023)
- Lingli Liang (ORCID: https://orcid.org/0000-0001-7594-387X)
- Chenming Sun (ORCID: https://orcid.org/0000-0002-6199-7225)
- Lina Sun (ORCID: https://orcid.org/0009-0008-5650-7480)
- Zhihong Yao (ORCID: https://orcid.org/0000-0001-5999-4466)
- Xiaobo Zhou (ORCID: https://orcid.org/0000-0002-7127-2869)
- Hao Ping (ORCID: https://orcid.org/0000-0003-2912-0965)
- Renyi Ding (ORCID: https://orcid.org/0000-0001-5194-8625)
- Lin Shi (ORCID: https://orcid.org/0000-0001-7578-7440)
- Tianzhe Zhang (ORCID: https://orcid.org/0000-0002-7114-3573)
- Baojun Zhang (ORCID: https://orcid.org/0000-0001-5972-1011)
- Dan Zhang (ORCID: https://orcid.org/0000-0001-9055-1954)
- Ruonan Liu (ORCID: https://orcid.org/0000-0001-9181-6934)
- Ge Yao (ORCID: https://orcid.org/0000-0002-3880-2987)
- Yanhong Su
- Lianjun Zhang (ORCID: https://orcid.org/0000-0001-9448-7718)
- Qianhao Wang (ORCID: https://orcid.org/0000-0002-1852-4369)
- Linbo Lan
- Boxiao He
Institutions
- Ministry of Education of the People's Republic of China (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Weinan Normal University (CN)
- Handan Polytechnic College (CN)
- Suzhou Institute of Systems Medicine (CN)
- Xi'an University of Technology (CN)
- Hanzhong People's Hospital (CN)
- Ministry of Education (TW)
- China XD Group (China) (CN)
- Hanzhong Central Hospital (CN)
- Xi'an Jiaotong University (CN)
Publication Details
- Journal
- Cell Death and Disease
- Published
- 2025-04-15
- DOI
- https://doi.org/10.1038/s41419-025-07606-z
- Citations
- 2
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 1.61