NAT10 accelerates pulmonary fibrosis through N4-acetylated TGFB1-initiated epithelial-to-mesenchymal transition upon ambient fine particulate matter exposure
NAT10 accelerates pulmonary fibrosis through N4-acetylated TGFB1-initiated epithelial-to-mesenchymal transition upon ambient fine particulate matter exposure
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DOI：
10.1016/j.envpol.2023.121149
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发表时间：
2023-02-09
影响因子：
8.9
通讯作者：
Chen，Rui
中科院分区：
文献类型：
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作者：
Wu，Shenshen;Yin，Lijia;Chen，Rui
暴露于环境细颗粒物（PM2.5）与更高的肺纤维化风险有关。在纤维化发展过程中，表转录组的失调导致mrna的异常表达。n4 -乙酰胞苷（ac4C）是最常见的RNA表观遗传改变之一，然而，其在pm2.5引发的纤维化中的功能尚不清楚。本研究建立肺上皮和小鼠模型，暴露于pm2.5中，分析ac4C改变在肺纤维化中的功能及其机制。与此同时，与对照组相比，唯一已知的ac4C“writer”蛋白n -乙酰转移酶10 （N-acetyltransferase 10, NAT10）在肺上皮中的表达水平被显著诱导。随后，NAT10增强了转化生长因子β 1(TGFB1) mRNA和蛋白水平的稳定性。作为上游驱动因子，TGFB1加速了EMT和纤维化过程。抑制NAT10可显著保护肺EMT和由pm2.5暴露驱动的纤维化，而TGFB1过表达逆转了NAT10抑制的保护作用。因此，NAT10以ac4c依赖的方式通过增加tgfb1mrna的稳定性来加速pm2.5引发的肺纤维化。我们的研究结果揭示了nat10调控的mRNA ac4C乙酰化在pm2.5引发的肺纤维化中的关键作用，并揭示了潜在的表转录机制。
Exposure to ambient fine particulate matter (PM2.5) has been linked to a higher pulmonary fibrosis risk. Dysregulation of the epitranscriptome results in abnormal expression of mRNAs during fibrosis development. N4-acetylcytidine (ac4C) is one of the most frequent RNA epigenetic alterations, however, its function in PM2.5-triggered fibrosis is yet unknown. In this study, lung epithelial and murine models were established and exposed to PM2.5to analyze the function of ac4C alteration in pulmonary fibrosis and underlying mechanisms. Meanwhile, the expression levels of only known ac4C “writer” protein, N-acetyltransferase 10 (NAT10), were significantly induced in pulmonary epithelia, relative to the control. Subsequently, NAT10 enhanced the stability oftransforming growthfactor beta1(TGFB1) mRNA as well as protein levels. As an up-stream driver, TGFB1 accelerated EMT and fibrosis process. Inhibition of NAT10 significantly protected against pulmonary EMT and fibrosis driven by PM2.5exposure, whereas TGFB1 overexpression reversed the protective effects of NAT10 inhibition. Thus, NAT10 accelerated PM2.5-triggered pulmonary fibrosis via increasingTGFB1mRNA stability in an ac4C-dependent manner. Our results reveal a pivotal role of NAT10-regulated mRNA ac4C acetylation in PM2.5-triggered pulmonary fibrosis and uncover the potential epitranscriptional mechanism.