METTL3 governs thymocyte development and thymic involution by regulating ferroptosis.

IF 17 Q1 CELL BIOLOGY
Huiru Jing, Jiayu Song, Jie Sun, Shaojun Su, Jin Hu, Haojian Zhang, Yanmin Bi, Bing Wu
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Abstract

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.

METTL3 通过调节铁蛋白沉积来控制胸腺细胞的发育和胸腺的消退。
鉴于胸腺在免疫衰老中的核心作用,确定胸腺内缩的调节因子非常重要。虽然传统的程序性细胞死亡在胸腺细胞发育过程中起着基础性作用,但细胞死亡途径如何促进胸腺衰老还不清楚。在这项研究中,我们发现CD4+CD8+双阳性(DP)胸腺细胞在进行胸腺内陷的老年小鼠中获得了衰老的特征,而富集在年轻小鼠DP细胞中的m6A甲基转移酶样蛋白3(METTL3)的表达却随着衰老而减少。通过有条件地删除 T 细胞中的 METTL3,我们揭示了 METTL3 在 DP 细胞存活以及通过谷胱甘肽过氧化物酶 4 阻止铁变态信号传导从而抑制 DP 胸腺细胞衰老特征方面的关键作用。从机理上讲,谷胱甘肽过氧化物酶 4 是由 METTL3 在翻译水平上维持的,与其甲基转移酶活性无关。此外,我们还发现,药物抑制铁突变可促进 DP 细胞存活,并减轻 DP 胸腺细胞的衰老特征。这些发现揭示了 METTL3 调控的铁突变在胸腺衰退中的作用,并确定了恢复胸腺功能的策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
14.70
自引率
0.00%
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