ATM-CHK2-Beclin 1 axis promotes autophagy to maintain ROS homeostasis under oxidative stress
ATM-CHK2-Beclin 1 axis promotes autophagy to maintain ROS homeostasis under oxidative stress
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ATM-CHK2-Beclin 1轴促进自噬以维持氧化应激下ROS稳态
DOI：
10.15252/embj.2019103111
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发表时间：
2020-03-18
期刊：
影响因子：
11.4
通讯作者：
Cao, Liu
中科院分区：
文献类型：
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作者：
Guo, Qi-Qiang;Wang, Shan-Shan;Cao, Liu
氧化应激与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发挥着重要作用。然而，其调控途径和结果仍未完全明晰。在此，我们表明活性氧（ROS）作为信号分子，通过共济失调毛细血管扩张突变蛋白（ATM）和细胞周期检查点激酶2（CHK2）来调节自噬，ATM和CHK2是在代谢和缺氧应激过程中被激活的DNA损伤应答（DDR）途径的一部分。我们报告称，CHK2与Beclin 1结合并使其在Ser90/Ser93位点磷酸化，从而以依赖ROS的方式破坏Beclin 1 - Bcl - 2自噬调节复合物的形成。我们进一步证明，CHK2介导的自噬通过清除受损线粒体，在降低ROS水平方面发挥了意想不到的作用，这是应激条件下细胞存活所必需的。最后，在脑卒中模型中，CHK2基因敲除（CHK2⁻/⁻）小鼠表现出更严重的梗死表型，且Beclin 1的p - Ser90/Ser93水平降低，这表明CHK2诱导的自噬在体内对细胞存活具有重要作用。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，可保护处于病理状况下的细胞免受应激诱导的组织损伤。
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.