RNA methylation into m(1)A era: a new regulation over T-cell function.
RNA methylation into m(1)A era: a new regulation over T-cell function.
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DOI：
10.1038/s41392-023-01360-4
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发表时间：
2023-02-22
影响因子：
39.3
通讯作者：
Wu, Min
中科院分区：
文献类型：
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作者：
Lin, Ping;Li, Guoping;Wu, Min
在最近发表在《自然免疫学》上的一篇论文中，刘等人。据描述，“作者”TRMT6/TRMT61A 复合物介导转移 RNA (tRNA) m1A 修饰，在激活后立即促进 T 细胞增殖必需的某些蛋白质的有效翻译，1 证明 tRNA m1A 甲基化作为关键的翻译检查点，为通过操纵 m1A 机制治疗 T 细胞相关炎症或癌症的新型免疫疗法铺平了道路。作为适应性免疫的一部分，CD4+ T 细胞发挥着重要作用。为了提供足够的免疫防御，幼稚T细胞需要在抗原刺激后及时合成大量功能蛋白，以适应退出静止状态并进行大规模克隆扩张和分化所需的生物能和生物合成需求的急剧增加（图1）。 1 过去几年的研究在了解抗原刺激后 T 细胞激活机制方面取得了重大进展，2 这一机制在转录水平上已得到广泛了解。然而，人们对蛋白质翻译的其他阶段（尤其是 tRNA 介导的翻译）如何影响 T 细胞反应知之甚少。长期以来人们一直认为 tRNA 通过与 mRNA 密码子的相互作用来影响翻译。最近，基于 tRNA N1-甲基腺苷修饰 (m1A) 的翻译控制模型解释了蛋白质合成调控。 “编写器”TRMT6/TRMT61A 复合物产生的 tRNA 中的 m1A 修饰可实现 mRNA 的有效翻译延伸。基于该模型，以及T细胞激活过程中大量蛋白质合成需求的困境，Liu等人。假设 tRNA-m1A 修饰可能有助于加速 mRNA 翻译效率和蛋白质合成，从而确保 T 细胞快速增殖。为此，他们在四个不同的激活阶段（即早期信号激活、代谢重编程、前细胞周期和增殖）进行了时间点 RNA 测序和 tRNA 测序。结果表明，早期T细胞激活以翻译事件为主，大多数tRNA和tRNA加工相关基因的表达大幅上调。此外，他们发现 Trmt61a 和 Trmt6 在 T 细胞激活后迅速上调。在生理条件下，m1A writer 的增加可能会产生两种影响：一是导致 tRNA 库内的修饰按比例增加，二是随着整体 tRNA 水平的增加，将修饰维持在与初始细胞中 tRNA 相同的比例。受益于m1A检测技术的最新进展，3作者进行了tRNA甲基化测序来检测T细胞中的tRNA-m1A水平，发现T细胞激活期间一般tRNA m1A水平稳定，这意味着TRMT6/TRMT61A复合物被放大以在T细胞激活时维持相同比例的m1A tRNA修饰水平。经过一系列体外和体内测试，作者证明tRNA-m1A58通过调节某些细胞周期mRNA的翻译延伸来促进T细胞的快速增殖和及时的免疫反应（图1）。 Trmt61a 缺失导致 CD4+ T 细胞中大多数 tRNA 的 m1A58 修饰水平显着降低，翻译解码能力显着降低，最终阻断许多关键蛋白的翻译，特别是 MYC，一种在 CD4+ T 细胞激活过程中必须快速表达的转录因子。 MYC 蛋白质水平降低会导致……的破坏
In a recent paper published in Nature Immunology, Liu et al. described that the “writers” TRMT6/TRMT61A complex mediated transfer RNA (tRNA) m1A modification, facilitating competent translation of certain proteins fundamental to T-cell proliferation in an instant upon activation, 1 demonstrating that tRNA m1A methylation as a crucial translational checkpoint paves the way for novel immunotherapies to treat T-cell-related inflammation or cancer via manipulating the m1A machinery. As part of adaptive immunity, CD4+ T cells play an instrumental role. In order to provide adequate immune defense, naïve T cells require the timely synthesis of a large number of functional proteins upon antigen stimulation so as to accommodate the drastic increase in bioenergetic and biosynthetic demands necessary to exit quiescent state and undergo massive clonal expansion and differentiation (Fig. 1). 1 Researches in the past few years have led to significant progress toward understanding the mechanism of T-cell activation upon antigen stimulation, 2 which has been extensively learned on the transcriptional level. However, little is known about how other phases of protein translation, especially tRNA-mediated translation, affect T-cell responses. It has long been believed that tRNAs influence translation through their interactions with the codons on mRNA. Recently, a translation control model based on N1-methyladenosine modification (m1A) of tRNAs explains the protein synthesis regulation. m1A modification in tRNA produced by “writers” TRMT6/TRMT61A complexes allow efficient translation elongation of mRNAs. Based on this model, as well as the dilemma of massive protein synthesis demand during T-cell activation, Liu et al. hypothesized that tRNA-m1A modification may contribute to accelerated mRNA translation efficiency and protein synthesis, thus ensuring rapid T-cell proliferation. To this end, they performed time point RNA-sequencing and tRNA-sequencing at four different stages of activation, namely early signaling activation, metabolic reprogramming, pre-cell-cycling, and proliferation. The results demonstrated that early T-cell activation was dominated by translation events, and the expressions of most tRNAs and tRNA processing-related genes were greatly upregulated. Furthermore, they found that Trmt61a and Trmt6 were rapidly upregulated upon T-cell activation. Under physiological conditions, the increase of m1A writers may have two effects: one is to cause a proportional increase in the modification within the tRNA pool, and the other is to maintain the modification at the same proportions as seen on the tRNA in naïve cells as global tRNA levels increase. Benefitted from the recent progress on the m1A detection technology, 3 the authors performed tRNA methylation sequencing to detect the tRNA-m1A levels in T cells, and found that general tRNA m1A level was steady during T-cell activation, implying that TRMT6/TRMT61A complex is scaled up to maintain the same proportions of m1A tRNA modification levels upon T-cell activation. After a series of in vitro and in vivo tests, the authors proved that tRNA-m1A58 prompted the rapid proliferation of T cells and timely immune responses by regulating the translation elongation of certain cell cycling mRNAs (Fig. 1). Trmt61a depletion results in a significant reduction in the m1A58 modification level of most tRNAs in CD4+ T cells and a significant decrease in translational decoding ability, ultimately blocking the translation of numerous key proteins, particularly MYC, a transcription factor that must be expressed rapidly during CD4+ T-cell activation. The reduced protein level of MYC results in disruption of …
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影响因子：
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作者：
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通讯作者：
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影响因子：
30.5
作者：
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影响因子：
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