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<p>The emerging field of epitranscriptomics is reshaping our understanding of post-transcriptional gene regulation in inflammatory diseases. <i>N</i><sup>4</sup>-acetylcytidine (ac<sup>4</sup>C), the only known acetylation modification in RNA catalyzed by <i>N</i>-acetyltransferase 10 (NAT10), is known to enhance mRNA stability and translation, yet its role in inflammatory bowel disease (IBD) remains unclear. In this study, we discovered that <i>Nat10</i> expression correlates with inflammatory and apoptotic pathways in human ulcerative colitis CD4<sup>+</sup> T cells. Our further analysis revealed that the deficiency of NAT10 led to a disruption of T cell development at steady state, and identified a pivotal role for NAT10 in preserving the pathogenicity of naïve CD4<sup>+</sup> T cells to induce adoptive transfer colitis. Mechanistically, the lack of NAT10 triggers the diminished stability of the anti-apoptotic gene BCL2-associated athanogene 3 (<i>Bag3</i>), initiating a cascade of events that includes the upregulation of apoptosis-related genes and an accelerated rate of apoptosis in T cells. Our findings reveal a previously unrecognized role of the NAT10-ac<sup>4</sup>C-<i>Bag3</i> axis in preserving T cell balance and suggests that targeting RNA ac<sup>4</sup>C modification could be a promising therapeutic approach for IBD.</p>

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RNA cytidine acetyltransferase NAT10 maintains T cell pathogenicity in inflammatory bowel disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月4日

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  • Haixin Li,
  • Xuemin Cai,
  • Changfen Xu,
  • Xinhui Yang,
  • Xiaohan Song,
  • Yuxin Kong,
  • Mei Yang,
  • Qielan Wu,
  • Song Guo Zheng,
  • Yiming Shao,
  • Ping Wang,
  • Jing Zhou,
  • Hua-Bing Li

摘要

The emerging field of epitranscriptomics is reshaping our understanding of post-transcriptional gene regulation in inflammatory diseases. N4-acetylcytidine (ac4C), the only known acetylation modification in RNA catalyzed by N-acetyltransferase 10 (NAT10), is known to enhance mRNA stability and translation, yet its role in inflammatory bowel disease (IBD) remains unclear. In this study, we discovered that Nat10 expression correlates with inflammatory and apoptotic pathways in human ulcerative colitis CD4+ T cells. Our further analysis revealed that the deficiency of NAT10 led to a disruption of T cell development at steady state, and identified a pivotal role for NAT10 in preserving the pathogenicity of naïve CD4+ T cells to induce adoptive transfer colitis. Mechanistically, the lack of NAT10 triggers the diminished stability of the anti-apoptotic gene BCL2-associated athanogene 3 (Bag3), initiating a cascade of events that includes the upregulation of apoptosis-related genes and an accelerated rate of apoptosis in T cells. Our findings reveal a previously unrecognized role of the NAT10-ac4C-Bag3 axis in preserving T cell balance and suggests that targeting RNA ac4C modification could be a promising therapeutic approach for IBD.