上海交通大学沈少明等研究人员合作发现，tRNA-GCN2-FBXO22轴介导的mTOR泛素化感知氨基酸不足。相关论文于2023年11月17日在线发表在《细胞—代谢》杂志上。

研究人员报告了单独或联合消耗细胞氨基酸会导致哺乳动物雷帕霉素靶标复合体 1（mTORC1）泛素化，从而通过阻止底物招募来抑制mTORC1激酶的活性。从机理上讲，氨基酸耗竭会导致不带电的tRNA累积，从而刺激GCN2磷酸化 FBXO22，FBXO22反过来又会在细胞质中累积，并以K27链接的方式在Lys2066处泛素化mTOR。因此，mTOR Lys2066的突变会取消mTOR在氨基酸缺乏时的泛素化，从而使mTOR在体外和体内对氨基酸饥饿不敏感。总之，这些数据揭示了mTORC1通过以前未知的GCN2-FBXO22-mTOR通路感知氨基酸的新机制，该通路由不带电的tRNA独特地控制。

据悉，mTORC1监测细胞氨基酸变化以实现功能，但这一过程的分子介质仍未完全明确。

附：英文原文

Title: The tRNA-GCN2-FBXO22-axis-mediated mTOR ubiquitination senses amino acid insufficiency

Author: Meng-Kai Ge, Cheng Zhang, Na Zhang, Ping He, Hai-Yan Cai, Song Li, Shuai Wu, Xi-Li Chu, Yu-Xue Zhang, Hong-Ming Ma, Li Xia, Shuo Yang, Jian-Xiu Yu, Shi-Ying Yao, Xiao-Long Zhou, Bing Su, Guo-Qiang Chen, Shao-Ming Shen

Issue&Volume: 2023-11-17

Abstract: Mammalian target of rapamycin complex 1 (mTORC1) monitors cellular amino acid changesfor function, but the molecular mediators of this process remain to be fully defined.Here, we report that depletion of cellular amino acids, either alone or in combination,leads to the ubiquitination of mTOR, which inhibits mTORC1 kinase activity by preventingsubstrate recruitment. Mechanistically, amino acid depletion causes accumulation ofuncharged tRNAs, thereby stimulating GCN2 to phosphorylate FBXO22, which in turn accruesin the cytoplasm and ubiquitinates mTOR at Lys2066 in a K27-linked manner. Accordingly,mutation of mTOR Lys2066 abolished mTOR ubiquitination in response to amino acid depletion,rendering mTOR insensitive to amino acid starvation both in vitro and in vivo. Collectively, these data reveal a novel mechanism of amino acid sensing by mTORC1via a previously unknown GCN2-FBXO22-mTOR pathway that is uniquely controlled by unchargedtRNAs.

DOI: 10.1016/j.cmet.2023.10.016

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(23)00385-6