The homeostatic link between oxidative stress and autophagy plays an important role in cellular responses to a wide variety of physiological and pathological conditions. However, the regulatory pathway and outcomes remain incompletely understood. Here, we show that reactive oxygen species (ROS) function as signaling molecules that regulate autophagy through ataxia-telangiectasia mutated (ATM) and cell cycle checkpoint kinase 2 (CHK2), a DNA damage response (DDR) pathway activated during metabolic and hypoxic stress. We report that CHK2 binds to and phosphorylates Beclin 1 at Ser90/Ser93, thereby impairing Beclin 1-Bcl-2 autophagy-regulatory complex formation in a ROS-dependent fashion. We further demonstrate that CHK2-mediated autophagy has an unexpected role in reducing ROS levels via the removal of damaged mitochondria, which is required for cell survival under stress conditions. Finally, CHK2-/- mice display aggravated infarct phenotypes and reduced Beclin 1 p-Ser90/Ser93 in a cerebral stroke model, suggesting an in vivo role of CHK2-induced autophagy in cell survival. Taken together, these results indicate that the ROS-ATM-CHK2-Beclin 1-autophagy axis serves as a physiological adaptation pathway that protects cells exposed to pathological conditions from stress-induced tissue damage.

中文翻译：

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ATM-CHK2-Beclin 1轴促进自噬以在氧化应激下维持ROS稳态。

氧化应激和自噬之间的稳态联系在细胞对多种生理和病理状况的反应中起着重要作用。但是，监管途径和结果仍然不完全了解。在这里，我们显示活性氧（ROS）作为信号分子，通过共济失调毛细血管扩张突变（ATM）和细胞周期检查点激酶2（CHK2）调节自噬，这是一种在代谢和低氧应激期间激活的DNA损伤反应（DDR）途径。我们报告CHK2绑定并磷酸化Sec90 / Ser93的Beclin 1，从而以ROS依赖的方式损害Beclin 1-Bcl-2自噬调节复合物的形成。我们进一步证明CHK2介导的自噬在通过去除受损的线粒体来降低ROS水平方面具有意想不到的作用，这是应激条件下细胞存活所必需的。最后，CHK2-/-小鼠在脑卒中模型中显示出梗塞表型加重和Beclin 1 p-Ser90 / Ser93减少，表明CHK2诱导的自噬在细胞存活中的体内作用。综上所述，这些结果表明，ROS-ATM-CHK2-Beclin 1自噬轴是一种生理适应途径，可以保护暴露于病理条件下的细胞免受应力诱导的组织损伤。