ATM-CHK2-Beclin 1 axis promotes autophagy to maintain ROS homeostasis under oxidative stress

被引：112

作者：

Guo, Qi-Qiang ^{[1
]}

Wang, Shan-Shan ^{[1
]}

Zhang, Shan-Shan ^{[1
]}

Xu, Hong-De ^{[1
]}

Li, Xiao-Man ^{[1
]}

Guan, Yi ^{[1
]}

Yi, Fei ^{[1
]}

Zhou, Ting-Ting ^{[1
]}

Jiang, Bo ^{[1
]}

Bai, Ning ^{[1
]}

Ma, Meng-Tao ^{[1
]}

Wang, Zhuo ^{[1
]}

Feng, Yan-Ling ^{[1
]}

Guo, Wen-Dong ^{[1
]}

Wu, Xuan ^{[1
]}

Zhao, Gui-Feng ^{[2
,3
]}

Fan, Guang-Jian ^{[4
]}

Zhang, Sheng-Ping ^{[4
]}

Wang, Chuan-Gui ^{[4
]}

Cao, Long-Yue ^{[5
]}

O'Rourke, Brian P. ^{[6
]}

Liu, Shi-Hui ^{[7
]}

Wang, Ping-Yuan ^{[8
]}

Han, Shuai ^{[9
]}

Song, Xiao-Yu ^{[1
]}

Cao, Liu ^{[1
]}

机构：

[1] China Med Univ, Liaoning Prov Collaborat Innovat Ctr Aging Relate, Minist Educ,Inst Translat Med, Key Lab Med Cell Biol,Minist Publ Hlth,Key Lab Ce, Shenyang, Peoples R China

[2] China Med Univ, ShengJing Hosp, Dept Expt Oncol, Shenyang, Peoples R China

[3] China Med Univ, ShengJing Hosp, Anim Ctr, Key Lab Res & Applicat Anim Models Environm & Met, Shenyang, Peoples R China

[4] Shanghai Jiao Tong Univ, Sch Med, Shanghai Gen Hosp, Inst Translat Med, Shanghai, Peoples R China

[5] Albert Einstein Coll Med, Dept Med Cardiol, Wilf Family Cardiovasc Res Inst, Bronx, NY 10467 USA

[6] Albert Einstein Coll Med, Dept Physiol & Biophys, Bronx, NY 10467 USA

[7] Univ Pittsburgh, Sch Med, Dept Med, Aging Inst, Pittsburgh, PA 15213 USA

[8] NHLBI, Cardiovasc Branch, NIH, Bldg 10, Bethesda, MD 20892 USA

[9] China Med Univ, Hosp 1, Dept Neurosurg, Shenyang, Peoples R China

来源：

EMBO JOURNAL | 2020年 / 39卷 / 10期

关键词：

autophagy; Beclin; 1; CHK2; oxidative stress; ROS; KINASE-MEDIATED PHOSPHORYLATION; DNA-DAMAGE; REGULATES AUTOPHAGY; PROTEIN-KINASE; CELL-CYCLE; BECLIN; ATM; MECHANISMS; AMPK; TUMORIGENESIS;

D O I：

10.15252/embj.2019103111

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页数：17

共 55 条

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