复旦大学武多娇研究团队提出了胞苷mRNA被NAT10乙酰化在T细胞扩增和抗病毒免疫中的关键作用。该项研究成果发表在2025年3月5日出版的《自然—免疫学》上。

课题组人员发现，在T细胞活化过程中，细胞上调N-乙酰基转移酶10（NAT10）的表达，这是一种负责mRNA的N⁴ -乙酰胞苷（ac⁴C）修饰的酶。ac⁴c修饰的Myc mRNA具有更高的翻译效率，能够快速合成MYC蛋白，支持T细胞扩增。在急性淋巴细胞性脉络丛脑膜炎病毒模型中，无主题T细胞中Nat10的条件缺失会导致MYC缺乏导致严重的细胞周期阻滞和细胞扩增限制，最终加剧感染。此外，NAT10水平较低的老年人的T细胞表现出增殖缺陷，这可能部分解释了老年人抗病毒反应受损的原因。该研究揭示了T细胞扩增、信号依赖性mRNA降解诱导的机制，以及ac⁴C修饰在T细胞介导的免疫应答中的潜在体内生物学意义。

研究人员表示，激活后，初始T细胞退出静止状态，需要全局翻译以快速扩增，但潜在的机制尚不清楚。

附：英文原文

Title: A critical role of N4-acetylation of cytidine in mRNA by NAT10 in T cell expansion and antiviral immunity

Author: Sun, Lu, Li, Xiaoyan, Xu, Feixiang, Chen, Yuwen, Li, Xushuo, Yang, Zhicheng, Yang, Ying, Wang, Ke, Ren, Tianyi, Lin, Zihao, Wang, Hua, Wang, Xiangdong, Lu, Yan, Song, Zhenju, Cheng, Zhou-Li, Wu, Duojiao

Issue&Volume: 2025-03-05

Abstract: Following activation, naive T cells exit quiescence and require global translation for rapid expansion, yet the underlying mechanisms remain unclear. Here, we show that during T cell activation, cells upregulate the expression of N-acetyltransferase 10 (NAT10), an enzyme responsible for N⁴-acetylcytidine (ac⁴C) modification of mRNAs. ac⁴C-modified Myc mRNAs show higher translation efficiency, enabling rapid synthesis of MYC protein and supporting robust T cell expansion. Conditional deletion of Nat10 in mouse T cells causes severe cell cycle arrest and limitation of cell expansion due to MYC deficiency, ultimately exacerbating infection in an acute lymphocytic choriomeningitis virus model. Additionally, T cells from older individuals with lower NAT10 levels show proliferative defects, which may partially account for impaired antiviral responses in older individuals. This study reveals a mechanism governing T cell expansion, signal-dependent mRNA degradation induction and the potential in vivo biological significance of ac⁴C modification in T cell-mediated immune responses.

DOI: 10.1038/s41590-025-02100-2

Source: https://www.nature.com/articles/s41590-025-02100-2