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<p>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 <i>N</i>-acetyltransferase 10 (NAT10), an enzyme responsible for <i>N</i><sup>4</sup>-acetylcytidine (ac<sup>4</sup>C) modification of mRNAs. ac<sup>4</sup>C-modified <i>Myc</i> mRNAs show higher translation efficiency, enabling rapid synthesis of MYC protein and supporting robust T cell expansion. Conditional deletion of <i>Nat10</i> 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 ac<sup>4</sup>C modification in T cell-mediated immune responses.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年3月5日

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

摘要

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.