上海交通大学医学院Hua-Bing Li、重庆国际免疫研究院Yuzhang Wu、北京大学Chengqi Yi和耶鲁大学医学院Richard A. Flavell团队合作取得一项新成果。经过不懈努力，他们的研究发现tRNA-m1A修饰通过调控MYC蛋白合成促进T细胞扩增。该研究于2022年9月22日发表于国际学术期刊《自然-免疫学》杂志。

研究人员表明在T细胞从静止状态退出时，T细胞上调转移RNA(tRNA) m¹A58“编辑”蛋白TRMT61A和TRMT6，定义了 m¹A58 RNA修饰特定早期表达tRNA子集。这些m¹A修饰的早期tRNA提高了翻译效率，能够快速和必要地合成MYC和一组特定的关键功能蛋白。然后MYC蛋白引导初始T细胞从静止状态退出进入增殖状态，并在激活后促进T细胞快速扩增。在过继转移结肠炎小鼠模型中，小鼠CD4⁺ T细胞中Trmt61a基因的条件性缺失导致MYC蛋白缺乏和细胞周期停滞，在同源抗原刺激时破坏T细胞扩增并减轻结肠炎。该研究首次阐明了tRNA-m¹A58修饰在T细胞介导发病机制中的生理作用，并揭示了tRNA-m¹A58调控T细胞稳态和特定信号依赖性特异关键蛋白翻译的新机制。

据介绍，初始T细胞在被激活从休眠态转变为过度活跃状态时会发生根本变化，该过程需要通过转录和翻译从头产生蛋白质。然而，T细胞促进翻译的机制很大程度上依然未知。

附：英文原文

Title: tRNA-m1A modification promotes T cell expansion via efficient MYC protein synthesis

Author: Liu, Yongbo, Zhou, Jing, Li, Xiaoyu, Zhang, Xiaoting, Shi, Jintong, Wang, Xuefei, Li, Hao, Miao, Shan, Chen, Huifang, He, Xiaoxiao, Dong, Liting, Lee, Gap Ryol, Zheng, Junke, Liu, Ru-Juan, Su, Bing, Ye, Youqiong, Flavell, Richard A., Yi, Chengqi, Wu, Yuzhang, Li, Hua-Bing

Issue&Volume: 2022-09-22

Abstract: Naive T cells undergo radical changes during the transition from dormant to hyperactive states upon activation, which necessitates de novo protein production via transcription and translation. However, the mechanism whereby T cells globally promote translation remains largely unknown. Here, we show that on exit from quiescence, T cells upregulate transfer RNA (tRNA) m1A58 ‘writer’ proteins TRMT61A and TRMT6, which confer m1A58 RNA modification on a specific subset of early expressed tRNAs. These m1A-modified early tRNAs enhance translation efficiency, enabling rapid and necessary synthesis of MYC and of a specific group of key functional proteins. The MYC protein then guides the exit of naive T cells from a quiescent state into a proliferative state and promotes rapid T cell expansion after activation. Conditional deletion of the Trmt61a gene in mouse CD4+ T cells causes MYC protein deficiency and cell cycle arrest, disrupts T cell expansion upon cognate antigen stimulation and alleviates colitis in a mouse adoptive transfer colitis model. Our study elucidates for the first time, to our knowledge, the in vivo physiological roles of tRNA-m1A58 modification in T cell-mediated pathogenesis and reveals a new mechanism of tRNA-m1A58-controlled T cell homeostasis and signal-dependent translational control of specific key proteins.

DOI: 10.1038/s41590-022-01301-3

Source: https://www.nature.com/articles/s41590-022-01301-3