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. 2023 Nov 28;42(11):113402.
doi: 10.1016/j.celrep.2023.113402. Epub 2023 Nov 9.

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

Jingwei Liu  1 , Songming Lu  1 , Lixia Zheng  1 , Qiqiang Guo  1 , Liangzi Cao  1 , Yutong Xiao  1 , Di Chen  1 , Yu Zou  1 , Xu Liu  2 , Chengsi Deng  1 , Siyi Zhang  1 , Ruohan Yang  1 , Yubang Wang  1 , Ying Zhang  1 , Naijin Zhang  1 , Xiaoyu Song  3 , Chengzhong Xing  4 , Zhenning Wang  5 , Liu Cao  6
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Free article

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

Jingwei Liu et al. Cell Rep. .
Free article

Abstract

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.

Keywords: ATG7; CP: Cell biology; CP: Molecular biology; ROS; autophagy; ubiquitination.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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