2. Academic Validation
  3. A critical role of N4-acetylation of cytidine in mRNA by NAT10 in T cell expansion and antiviral immunity

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

  • Nat Immunol. 2025 Apr;26(4):619-634. doi: 10.1038/s41590-025-02100-2.
Lu Sun # 1 2,  Xiaoyan Li # 3 4,  Feixiang Xu # 5,  Yuwen Chen 6,  Xushuo Li 6,  Zhicheng Yang 6,  Ying Yang 6,  Ke Wang 6,  Tianyi Ren 7,  Zihao Lin 6,  Hua Wang 3,  Xiangdong Wang 1,  Yan Lu 8,  Zhenju Song 9 10,  Zhou-Li Cheng 11,  Duojiao Wu 12 13
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of Lung Inflammation and Injury, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 2 Department of Medical Oncology, Shanghai Cancer Center & Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
  • 3 Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
  • 4 Department of Geriatrics, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
  • 5 Department of Emergency Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 6 Jinshan Hospital Center for Tumor Diagnosis & Therapy, Jinshan Hospital, Fudan University, Shanghai, China.
  • 7 Department of Gastroenterology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 8 Institute of Metabolism and Regenerative Medicine, Digestive Endoscopic Center, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. luyan5011@shsmu.edu.cn.
  • 9 Shanghai Key Laboratory of Lung Inflammation and Injury, Zhongshan Hospital, Fudan University, Shanghai, China. song.zhenju@zs-hospital.sh.cn.
  • 10 Department of Emergency Medicine, Zhongshan Hospital, Fudan University, Shanghai, China. song.zhenju@zs-hospital.sh.cn.
  • 11 Jinshan Hospital Center for Tumor Diagnosis & Therapy, Jinshan Hospital, Fudan University, Shanghai, China. chengzhouli@fudan.edu.cn.
  • 12 Shanghai Key Laboratory of Lung Inflammation and Injury, Zhongshan Hospital, Fudan University, Shanghai, China. wu.duojiao@zs-hospital.sh.cn.
  • 13 Jinshan Hospital Center for Tumor Diagnosis & Therapy, Jinshan Hospital, Fudan University, Shanghai, China. wu.duojiao@zs-hospital.sh.cn.
  • # Contributed equally.
PMID: 40045031 DOI: 10.1038/s41590-025-02100-2
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.

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