YTHDF1区分了mTORC1在衰老过程中的作用。

YTHDF1 differentiates the contributing roles of mTORC1 in aging.

作者信息

Xu Chenzhong, Yu Cong, Zhang Jie, Zhang Zhen, Zhang Jin, Meng Yuan, Wang Ming, Wen Minting, Chen Junhao, Ning Yuping, Chen Xinchun, Gu Jinke, Su Wen, Liu Baohua

机构信息

Shenzhen Key Laboratory for Systemic Aging and Intervention (SKL-SAI), Shenzhen Key Laboratory of Anti-Aging and Regenerative Medicine (SKL-ARM), Guangdong Provincial Key Laboratory of Genome Stability and Disease Prevention, Marshall Laboratory of Biomedical Engineering, International Cancer Center, School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen 518055, China.

出版信息

Mol Cell. 2025 Jun 5;85(11):2194-2210.e8. doi: 10.1016/j.molcel.2025.05.003. Epub 2025 May 28.

DOI:10.1016/j.molcel.2025.05.003

PMID:40441158

Abstract

The mechanistic target of rapamycin (mTOR) serves as an essential hub in sensing metabolic stress and regulating aging, although the differential contributions of mTOR-regulated protein and cholesterol synthesis are unclear. Post-transcriptional modifications of mRNAs, such as N6-methyladenosine (m6A), occur rapidly in response to acute environmental changes to maintain tissue homeostasis. Here, we showed that loss of YTH m6A RNA-binding protein 1 (YTHDF1) accelerated murine aging. Mechanistically, YTHDF1 is anchored to the lysosome surface by lysosome-associated membrane protein (LAMP2), whereby it recruits tuberous sclerosis complex (TSC2) to inhibit mTOR complex 1 (mTORC1). Ythdf1 loss activated mTORC1-sterol regulatory element-binding protein 2 (SREBP2)-axis-mediated cholesterol biosynthesis but not m6A-reader-regulated protein translation. Rapamycin restored murine healthspan in contrast to the maximum lifespan shortening caused by Ythdf1 depletion. Our data reveal an m6A-independent function of YTHDF1, which differentiates the contributing roles of mTORC1 in the regulation of aging.

摘要

雷帕霉素的作用机制靶点（mTOR）是感知代谢应激和调节衰老的关键枢纽，尽管mTOR调节的蛋白质和胆固醇合成的不同作用尚不清楚。mRNA的转录后修饰，如N6-甲基腺苷（m6A），会在急性环境变化时迅速发生，以维持组织稳态。在此，我们表明YTH m6A RNA结合蛋白1（YTHDF1）的缺失加速了小鼠衰老。从机制上讲，YTHDF1通过溶酶体相关膜蛋白（LAMP2）锚定在溶酶体表面，从而招募结节性硬化复合物（TSC2）来抑制mTOR复合物1（mTORC1）。Ythdf1缺失激活了mTORC1-固醇调节元件结合蛋白2（SREBP2）轴介导的胆固醇生物合成，但未激活m6A阅读蛋白调节的蛋白质翻译。与Ythdf1缺失导致的最大寿命缩短相反，雷帕霉素恢复了小鼠的健康寿命。我们的数据揭示了YTHDF1的一种不依赖m6A的功能，这区分了mTORC1在衰老调节中的不同作用。