RNA Cytidine Acetyltransferase NAT10 Maintains T Cell Pathogenicity in Inflammatory Bowel Disease [ATAC-Seq]

The enzyme N-acetyltransferase 10 (NAT10), known as the exclusive catalyst for N4-acetylcytidine (ac4C) modification, has been associated with various cellular processes, including tRNA acetylation, 18S rRNA biogenesis, mRNA stability, and translational efficiency. Despite extensive investigation into its molecular mechanisms in vitro, the physiological function of NAT10 under normal conditions has remained largely undefined. In this study, we found 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 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 maintaining T cell homeostasis in vivo. Overall design: We isolated naïve CD4+ T cells from 3 WT and 3 Nat10 cKO mice for RNA-sequencing.

N-乙酰基转移酶10（以下简称NAT10）是N4-乙酰胞苷（以下简称ac4C）修饰的专属催化酶，参与包括转运RNA（tRNA）乙酰化、18S核糖体RNA（rRNA）生物发生、信使RNA（mRNA）稳定性调控以及翻译效率在内的多种细胞过程。尽管学界已对其体外分子机制开展了广泛研究，但正常生理状态下NAT10的生理学功能仍未得到明确阐释。本研究发现，NAT10缺失会破坏稳态下的T细胞发育，并证实NAT10在维持初始型CD4+ T细胞诱导过继转移性结肠炎的致病性中发挥关键作用。机制层面，NAT10缺失会导致抗凋亡基因Bag3的稳定性下降，进而引发一系列级联反应，包括凋亡相关基因的上调以及T细胞凋亡速率加快。本研究结果揭示了此前未被认知的NAT10-ac4C-Bag3轴在体内维持T细胞稳态中的作用。实验设计：我们从3只野生型（WT）小鼠和3只NAT10条件性敲除（cKO）小鼠中分离初始型CD4+ T细胞，用于RNA测序（RNA-sequencing）。