METTL3 governs thymocyte development and thymic involution by regulating ferroptosis

胸腺退化 胸腺细胞 内卷(密宗) CD8型 生物 细胞生物学 程序性细胞死亡 T细胞 调节器 免疫系统 衰老 免疫学 癌症研究 遗传学 细胞凋亡 神经科学 意识 基因
作者
Huiru Jing,Jiayu Song,Jie Sun,Shaojun Su,Jin Hu,Haojian Zhang,Yanmin Bi,Bing Wu
出处
期刊:Nature Aging
标识
DOI:10.1038/s43587-024-00724-x
摘要

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 m6A 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. By exploring the molecular regulation of thymic involution, Jing et al. uncover METTL3 as a regulator of CD4+CD8+ thymocyte survival and a target for restraining thymic involution through its modulation of ferroptosis signaling.
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