ALKBH5 SUMOylation介导的FBXW7 m6A修饰调节了1 - 尼托烯诱导的肺纤维化期间的膜细胞衰老

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Se-Ruo Li¹, Ning-Ning Kang², Rong-Rong Wang¹

¹Department 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.

Journal of hazardous materials

|February 16, 2024

概括

1-尼托烯 (1-NP) 通过破坏端粒并诱导细胞衰老,导致肺纤维化. 线粒体ROS触发了一条导致TRF2降解和纤维化的途径,提供了潜在的治疗点.

科学领域:

环境毒理学环境毒理学
细胞生物学细胞生物学
分子机制的分子机制

背景情况:

1-尼托 (1-NP) 是已知的环境污染物,可能导致肺纤维化.
1-NP诱导的肺纤维化背后的精确分子机制尚未完全阐明.
以前的研究表明,暴露于1-NP会导致小鼠的肺纤维化.

研究的目的:

为了研究1-尼特罗皮烯诱导肺纤维化的分子机制.
为了确定参与1-NP引起的肺损伤的关键细胞和分子事件.
探索1-NP诱导的肺纤维化潜在的治疗干预措施.

主要方法:

对小鼠和膜上皮细胞系暴露于1-尼托烯.
对端粒损伤,细胞衰老和蛋白质表达 (TRF2,FBXW7) 的评估.
调查泛化,蛋白质体降解,m6A修饰和SUMOylation路径.
利用线粒体向抗氧化剂Mito-TEMPO来评估其保护作用.

主要成果:

1-NP诱导的端粒损伤,细胞衰老和TRF2的下调,在肺组织和细胞中对FBXW7的上调.
1-NP诱导的TRF2降解取决于FBXW7 E3酶活性.
FBXW7上调涉及ALKBH5-YTHDF1-介导的m6A修饰,而1-NP促进了ALKBH5的SUMOylation和降解.
观察到线粒体ROS (mtROS) 的过度产生,而Mito-TEMPO治疗逆转了1-NP诱导的病理变化.

结论:

线粒体ROS启动了一连串涉及ALKBH5 SUMOylation和FBXW7 m6A的修饰,这对TRF2降解和1-NP诱导的肺纤维化中的细胞衰老至关重要.
这一途径突出了针对1-NP引起的肺纤维化进行干预的特定分子标.
这些发现为开发有针对性的疗法提供了机制基础,以减轻环境污染物引起的肺部疾病.

关键词:

1-NP是指一个NP.细胞衰老细胞衰老 FBXW7FBXW7FFBXW7FF FBXW7FFF FBXW7FF FBXW7F 在M6A中,它是M6A.肺部纤维化肺部纤维化这就是SUMOylation的作用.

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