tRNA-m1A modification promotes T cell expansion via efficient MYC protein synthesis
tRNA-m1A modification promotes T cell expansion via efficient MYC protein synthesis
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tRNA-m1A 修饰通过高效 MYC 蛋白合成促进 T 细胞扩增
DOI：
10.1038/s41590-022-01301-3
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发表时间：
2022-09-22
影响因子：
30.5
通讯作者：
Li, Hua-Bing
中科院分区：
文献类型：
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作者：
Liu, Yongbo;Zhou, Jing;Li, Hua-Bing
初始T细胞是静止的，但在抗原活化后经历动态变化。Li及其同事表明，tRNA甲基转移酶复合物TRMT 61 A-TRMT 6的上调和tRNA的N-1-甲基腺苷修饰有助于加速mRNA翻译效率，特别是MYC蛋白的翻译效率，并且是T细胞快速增殖所必需的。初始T细胞在激活后从休眠状态过渡到过度活跃状态期间发生根本性变化，这需要通过转录和翻译从头产生蛋白质。然而，T细胞全面促进翻译的机制在很大程度上仍然未知。在这里，我们表明，退出静止期，T细胞上调转运RNA（tRNA）m（1）A58 '作家'蛋白TRMT 61 A和TRMT 6，赋予m（1）A58 RNA修饰的早期表达的tRNA的特定子集。这些m（1）A修饰的早期tRNA提高了翻译效率，使MYC和一组特定的关键功能蛋白的快速和必要的合成成为可能。MYC蛋白然后引导幼稚T细胞从静止状态进入增殖状态，并促进活化后的快速T细胞扩增。在小鼠过继转移结肠炎模型中，小鼠CD 4（+）T细胞中Trmt 61 a基因的条件性缺失导致MYC蛋白缺陷和细胞周期停滞，破坏同源抗原刺激后的T细胞扩增并使结肠炎恶化。我们的研究首次阐明了tRNA-m（1）A58修饰在T细胞介导的发病机制中的体内生理作用，并揭示了tRNA-m（1）A58控制T细胞稳态和信号依赖性翻译控制特定关键蛋白的新机制。
Naive T cells are quiescent but undergo dynamic changes upon antigenic activation. Li and colleagues show that upregulation of tRNA methyltransferase complex TRMT61A-TRMT6 and N-1-methyladenosine modification of tRNAs contribute to accelerated mRNA translation efficiency, in particular that of MYC protein, and are required for rapid T cell proliferation.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) m(1)A58 'writer' proteins TRMT61A and TRMT6, which confer m(1)A58 RNA modification on a specific subset of early expressed tRNAs. These m(1)A-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-m(1)A58 modification in T cell-mediated pathogenesis and reveals a new mechanism of tRNA-m(1)A58-controlled T cell homeostasis and signal-dependent translational control of specific key proteins.