Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230601, China; Institute of Respiratory Diseases, Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230601, China.
Department of Thoracic Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China.
J Hazard Mater. 2024 Apr 15;468:133704. doi: 10.1016/j.jhazmat.2024.133704. Epub 2024 Feb 9.
Our previous study revealed that 1-nitropyrene (1-NP) exposure evoked pulmonary fibrosis in mice. However, the exact mechanism remained elusive. We found that 1-NP induced telomere damage and cellular senescence in mice lungs, and two alveolar epithelial cells lines. 1-NP downregulated telomere repeat binding factor 2 (TRF2), and upregulated FBXW7. Mechanistically, 1-NP-caused TRF2 ubiquitination and proteasomal degradation depended on E3 ubiquitin ligase activity of FBXW7. Moreover, 1-NP upregulated FBXW7 m6A modification via an ALKBH5-YTHDF1-dependent manner. Further analysis suggested 1-NP promoted ALKBH5 SUMOylation and subsequent proteasomal degradation. Additionally, 1-NP evoked mitochondrial reactive oxygen species (mtROS) overproduction. Mito-TEMPO, a mitochondrial-targeted antioxidant, mitigated 1-NP-caused mtROS overproduction, ALKBH5 SUMOylation, FBXW7 m6A modification, TRF2 degradation, cellular senescence, and pulmonary fibrosis. Taken together, mtROS-initiated ALKBH5 SUMOylation and subsequent FBXW7 m6A modification is indispensable for TRF2 degradation and cellular senescence in alveolar epithelial cells during 1-NP-induced pulmonary fibrosis. Our study provides target intervention measures towards 1-NP-evoked pulmonary fibrosis.
我们之前的研究表明，1-硝基芘（1-NP）暴露会引起小鼠肺部纤维化。然而，确切的机制仍不清楚。我们发现 1-NP 诱导了小鼠肺部和两种肺泡上皮细胞系中的端粒损伤和细胞衰老。1-NP 下调了端粒重复结合因子 2（TRF2），上调了 FBXW7。在机制上，1-NP 引起的 TRF2 泛素化和蛋白酶体降解依赖于 FBXW7 的 E3 泛素连接酶活性。此外，1-NP 通过 ALKBH5-YTHDF1 依赖性方式上调了 FBXW7 的 m6A 修饰。进一步的分析表明，1-NP 促进了 ALKBH5 的 SUMO 化和随后的蛋白酶体降解。此外，1-NP 引起线粒体活性氧（mtROS）的过度产生。线粒体靶向抗氧化剂 Mito-TEMPO 减轻了 1-NP 引起的 mtROS 过度产生、ALKBH5 SUMO 化、FBXW7 m6A 修饰、TRF2 降解、细胞衰老和肺纤维化。总之，mtROS 引发的 ALKBH5 SUMO 化和随后的 FBXW7 m6A 修饰对于 1-NP 诱导的肺泡上皮细胞中的 TRF2 降解和细胞衰老至关重要。我们的研究为 1-NP 诱发的肺纤维化提供了靶向干预措施。
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