ATM ‐ CHK 2‐Beclin 1 axis promotes autophagy to maintain ROS homeostasis under oxidative stress
| Autor: | Longyue Cao, Meng-Tao Ma, Xiaoyu Song, Shengping Zhang, Brian P. O’Rourke, Qiqiang Guo, Wendong Guo, Tingting Zhou, Xuan Wu, Fei Yi, Shan-Shan Zhang, Shuai Han, Xiaoman Li, Zhuo Wang, Shan-Shan Wang, Shihui Liu, Chuangui Wang, Ning Bai, Ping-Yuan Wang, Gui-Feng Zhao, Hongde Xu, Guangjian Fan, Yi Guan, Liu Cao, Yanling Feng, Bo Jiang |
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| Rok vydání: | 2020 |
| Předmět: |
Cell signaling
Ataxia Telangiectasia Mutated Proteins Mitochondrion Biology medicine.disease_cause General Biochemistry Genetics and Molecular Biology Cell Line Mice 03 medical and health sciences 0302 clinical medicine Autophagy medicine Animals Humans Phosphorylation Molecular Biology Ischemic Stroke 030304 developmental biology chemistry.chemical_classification 0303 health sciences Reactive oxygen species General Immunology and Microbiology General Neuroscience Articles HCT116 Cells Cell biology Checkpoint Kinase 2 Disease Models Animal Oxidative Stress HEK293 Cells chemistry Beclin-1 Regulatory Pathway Reactive Oxygen Species 030217 neurology & neurosurgery Homeostasis Oxidative stress HeLa Cells |
| Zdroj: | EMBO J |
| ISSN: | 1460-2075 0261-4189 |
| DOI: | 10.15252/embj.2019103111 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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