CHK2 Promotes Metabolic Stress-Induced Autophagy through ULK1 Phosphorylation
Ran Guo,
Shan-Shan Wang,
Xiao-You Jiang,
Ye Zhang,
Yang Guo,
Hong-Yan Cui,
Qi-Qiang Guo,
Liu Cao,
Xiao-Chen Xie
Affiliations
Ran Guo
Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang 110004, China
Shan-Shan Wang
College of Basic Medical Science, Health Sciences Institute, Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang 110122, China
Xiao-You Jiang
College of Basic Medical Science, Health Sciences Institute, Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang 110122, China
Ye Zhang
College of Basic Medical Science, Health Sciences Institute, Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang 110122, China
Yang Guo
College of Basic Medical Science, Health Sciences Institute, Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang 110122, China
Hong-Yan Cui
College of Basic Medical Science, Health Sciences Institute, Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang 110122, China
Qi-Qiang Guo
College of Basic Medical Science, Health Sciences Institute, Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang 110122, China
Liu Cao
College of Basic Medical Science, Health Sciences Institute, Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang 110122, China
Xiao-Chen Xie
Liaoning Provincial Key Laboratory of Endocrine Diseases, Department of Endocrinology and Metabolism, Institute of Endocrinology, The First Affiliated Hospital of China Medical University, Shenyang 110001, China
Reactive oxygen species (ROS) act as a signaling intermediate to promote cellular adaptation to maintain homeostasis by regulating autophagy during pathophysiological stress. However, the mechanism by which ROS promotes autophagy is still largely unknown. Here, we show that the ATM/CHK2/ULK1 axis initiates autophagy to maintain cellular homeostasis by sensing ROS signaling under metabolic stress. We report that ULK1 is a physiological substrate of CHK2, and that the binding of CHK2 to ULK1 depends on the ROS signal and the phosphorylation of threonine 68 of CHK2 under metabolic stress. Further, CHK2 phosphorylates ULK1 on serine 556, and this phosphorylation is dependent on the ATM/CHK2 signaling pathway. CHK2-mediated phosphorylation of ULK1 promotes autophagic flux and inhibits apoptosis induced by metabolic stress. Taken together, these results demonstrate that the ATM/CHK2/ULK1 axis initiates an autophagic adaptive response by sensing ROS, and it protects cells from metabolic stress-induced cellular damage.
