A critical role of N4-acetylation of cytidine in mRNA by NAT10 in T cell expansion and antiviral immunity
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 N<sup>4</sup>-acetylcytidine (ac<sup>4</sup>C) modification of mRNAs. ac<sup>4</sup>C-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 ac<sup>4</sup>C modification in T cell-mediated immune responses.
Authors
- Yan Lü (ORCID: https://orcid.org/0000-0003-3468-2241)
- Zhicheng Yang (ORCID: https://orcid.org/0000-0001-5868-9814)
- Zhou‐Li Cheng (ORCID: https://orcid.org/0009-0002-1961-534X)
- Ying Yang (ORCID: https://orcid.org/0000-0002-8104-5985)
- Tianyi Ren (ORCID: https://orcid.org/0000-0002-0844-7072)
- Duojiao Wu (ORCID: https://orcid.org/0000-0003-2562-8825)
- Zhenju Song (ORCID: https://orcid.org/0000-0001-9294-8824)
- Zihao Lin
- Ke Wang (ORCID: https://orcid.org/0009-0004-9852-3842)
- Lu Sun (ORCID: https://orcid.org/0000-0001-7356-7866)
- Xiangdong Wang (ORCID: https://orcid.org/0000-0002-8406-7928)
- Hua Wang (ORCID: https://orcid.org/0000-0002-2605-5697)
- Yu‐Wen Chen (ORCID: https://orcid.org/0000-0002-4335-7574)
- Feixiang Xu (ORCID: https://orcid.org/0000-0001-6722-228X)
- Xushuo Li
- Xiaoyan Li (ORCID: https://orcid.org/0000-0002-8807-4199)
Institutions
- Sun Yat-sen University (CN)
- Shanghai Jiao Tong University (CN)
- Anhui Medical University (CN)
- Fudan University (CN)
- XinHua Hospital (CN)
- Fudan University Shanghai Cancer Center (CN)
- Jinshan Hospital of Fudan University (CN)
- Zhongshan Hospital (CN)
- The First Affiliated Hospital, Sun Yat-sen University (CN)
- First Affiliated Hospital of Anhui Medical University (CN)
- Shanghai Sixth People's Hospital (CN)
Publication Details
- Journal
- Nature Immunology
- Published
- 2025-03-05
- DOI
- https://doi.org/10.1038/s41590-025-02100-2
- Citations
- 14
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 11.28
Funders
- National Natural Science Foundation of China
- Science and Technology Commission of Shanghai Municipality