METTL3 governs thymocyte development and thymic involution by regulating ferroptosis.

Autor: Jing H; Department of Urology, State Key Laboratory of Virology, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.; Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, China., Song J; Department of Urology, State Key Laboratory of Virology, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.; Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, China., Sun J; Department of Urology, State Key Laboratory of Virology, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.; Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, China., Su S; Department of Urology, State Key Laboratory of Virology, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.; Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, China., Hu J; Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, China., Zhang H; Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, China., Bi Y; Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, China. ht000601@whu.edu.cn., Wu B; Department of Urology, State Key Laboratory of Virology, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China. bingwu@whu.edu.cn.; Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, China. bingwu@whu.edu.cn.
Jazyk: angličtina
Zdroj: Nature aging [Nat Aging] 2024 Oct 23. Date of Electronic Publication: 2024 Oct 23.
DOI: 10.1038/s43587-024-00724-x
Abstrakt: Given its central role in immune aging, it is important to identify the regulators of thymic involution. While conventional programmed cell death has a fundamental role in thymocyte development, how cell death pathways contribute to thymic involution are unclear. In this study, we found that CD4 + CD8 + double-positive (DP) thymocytes acquired the characteristics of senescence in aged mice undergoing thymic involution, while expression of the m 6 A methyltransferase-like protein 3 (METTL3), which is enriched in DP cells from young mice, decreased with aging. By conditionally deleting METTL3 in T cells, we revealed a critical role for METTL3 in DP cell survival and in restraining the features of aging in DP thymocytes by preventing ferroptosis signaling through glutathione peroxidase 4. Mechanistically, glutathione peroxidase 4 was maintained by METTL3 at the translational level, independently of its methyltransferase activity. Furthermore, we found that pharmacological inhibition of ferroptosis promoted DP cell survival and attenuated the features of aging in DP thymocytes. These findings uncover a role for METTL3-regulated ferroptosis in thymic involution and identify strategies to restore thymic function.
Competing Interests: Competing interests The authors declare no competing interests.
(© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze: MEDLINE
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