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ATM-CHK2-TRIM32 axis regulates ATG7 ubiquitination to initiate autophagy under oxidative stress

Jingwei Liu1, Songming Lu1, Lixia Zheng1

  • 1The 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.

Cell Reports
|November 9, 2023
PubMed

Insights

Reactive oxygen species (ROS) trigger autophagy by activating the ATM-CHK2-TRIM32 pathway, which ubiquitinates ATG7 to prevent cellular damage and maintain homeostasis.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Autophagy is a crucial cellular process for maintaining homeostasis and preventing damage.
  • Oxidative stress, indicated by reactive oxygen species (ROS), is implicated in cellular damage.
  • The precise molecular mechanisms initiating ROS-induced autophagy are not fully understood.

Purpose of the Study:

  • To elucidate the regulatory pathway initiating autophagy in response to oxidative stress.
  • To identify the role of the E3 ubiquitin ligase TRIM32 in ROS-mediated autophagy.
  • To establish the ATM-CHK2-TRIM32-ATG7 signaling axis in cellular protection.

Main Methods:

  • Investigated the phosphorylation and ubiquitination events in response to metabolic stress.
  • Utilized cell-based assays to examine protein interactions and modifications.
  • Employed a stroke model in Chk2 knockout mice to assess in vivo relevance.

Main Results:

  • ROS induce ATM and CHK2 phosphorylation, activating the pathway.
  • CHK2 phosphorylates TRIM32, which then ubiquitinates ATG7.
  • Chk2 knockout mice exhibited exacerbated infarction and reduced TRIM32 phosphorylation and ATG7 ubiquitination.

Conclusions:

  • A novel molecular mechanism for autophagy initiation via the ATM-CHK2-TRIM32-ATG7 axis is proposed.
  • This pathway is critical for maintaining intracellular homeostasis under stress.
  • The findings offer insights into protecting cells from stress-induced damage in pathological conditions.
Keywords:
ATG7CP: Cell biologyCP: Molecular biologyROSautophagyubiquitination

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