Cell Reports (Nov 2023)
ATM-CHK2-TRIM32 axis regulates ATG7 ubiquitination to initiate autophagy under oxidative stress
- Jingwei Liu,
- Songming Lu,
- Lixia Zheng,
- Qiqiang Guo,
- Liangzi Cao,
- Yutong Xiao,
- Di Chen,
- Yu Zou,
- Xu Liu,
- Chengsi Deng,
- Siyi Zhang,
- Ruohan Yang,
- Yubang Wang,
- Ying Zhang,
- Naijin Zhang,
- Xiaoyu Song,
- Chengzhong Xing,
- Zhenning Wang,
- Liu Cao
Affiliations
- Jingwei Liu
- The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province 110122, China; Key Laboratory of Cell Biology of Ministry of Public Health, Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, Liaoning Province 110122, China
- Songming Lu
- The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province 110122, China; Key Laboratory of Cell Biology of Ministry of Public Health, Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, Liaoning Province 110122, China
- Lixia Zheng
- The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province 110122, China; Key Laboratory of Cell Biology of Ministry of Public Health, Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, Liaoning Province 110122, China
- Qiqiang Guo
- The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province 110122, China; Key Laboratory of Cell Biology of Ministry of Public Health, Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, Liaoning Province 110122, China
- Liangzi Cao
- The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province 110122, China; Key Laboratory of Cell Biology of Ministry of Public Health, Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, Liaoning Province 110122, China
- Yutong Xiao
- The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province 110122, China; Key Laboratory of Cell Biology of Ministry of Public Health, Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, Liaoning Province 110122, China
- Di Chen
- The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province 110122, China; Key Laboratory of Cell Biology of Ministry of Public Health, Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, Liaoning Province 110122, China
- Yu Zou
- The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province 110122, China; Key Laboratory of Cell Biology of Ministry of Public Health, Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, Liaoning Province 110122, China
- Xu Liu
- Department of Neurology, First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province 110001, China
- Chengsi Deng
- The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province 110122, China; Key Laboratory of Cell Biology of Ministry of Public Health, Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, Liaoning Province 110122, China
- Siyi Zhang
- The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province 110122, China; Key Laboratory of Cell Biology of Ministry of Public Health, Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, Liaoning Province 110122, China
- Ruohan Yang
- The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province 110122, China; Key Laboratory of Cell Biology of Ministry of Public Health, Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, Liaoning Province 110122, China
- Yubang Wang
- The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province 110122, China; Key Laboratory of Cell Biology of Ministry of Public Health, Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, Liaoning Province 110122, China
- Ying Zhang
- The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province 110122, China; Key Laboratory of Cell Biology of Ministry of Public Health, Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, Liaoning Province 110122, China
- Naijin Zhang
- The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province 110122, China; Key Laboratory of Cell Biology of Ministry of Public Health, Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, Liaoning Province 110122, China
- Xiaoyu Song
- The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province 110122, China; Key Laboratory of Cell Biology of Ministry of Public Health, Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, Liaoning Province 110122, China; Corresponding author
- Chengzhong Xing
- Department of Anus and Intestine Surgery, First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province 110001, China; Corresponding author
- Zhenning Wang
- Key Laboratory of Cell Biology of Ministry of Public Health, Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, Liaoning Province 110122, China; Corresponding author
- Liu Cao
- The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province 110122, China; Key Laboratory of Cell Biology of Ministry of Public Health, Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, Liaoning Province 110122, China; Corresponding author
- Journal volume & issue
-
Vol. 42,
no. 11
p. 113402
Abstract
Summary: Oxidative stress-induced autophagy helps to prevent cellular damage and to maintain homeostasis. However, the regulatory pathway that initiates autophagy remains unclear. We previously showed that reactive oxygen species (ROS) function as signaling molecules to activate the ATM-CHK2 pathway and promote autophagy. Here, we find that the E3 ubiquitin ligase TRIM32 functions downstream of ATM-CHK2 to regulate ATG7 ubiquitination. Under metabolic stress, ROS induce ATM phosphorylation at S1981, which in turn phosphorylates CHK2 at T68. We show that CHK2 binds and phosphorylates TRIM32 at the S55 site, which then mediates K63-linked ubiquitination of ATG7 at the K45 site to initiate autophagy. In addition, Chk2−/− mice show an aggravated infarction phenotype and reduced phosphorylation of TRIM32 and ubiquitination of ATG7 in a stroke model. We propose a molecular mechanism for autophagy initiation by ROS via the ATM-CHK2-TRIM32-ATG7 axis to maintain intracellular homeostasis and to protect cells exposed to pathological conditions from stress-induced tissue damage.