ATR/Chk1 signaling induces autophagy through sumoylated RhoB-mediated lysosomal translocation of TSC2 after DNA damage

Mingdong Liu, Taoling Zeng, Xin Zhang, Chunyan Liu, Zhihui Wu, Luming Yao, Changchuan Xie, Hui Xia, Qi Lin, Liping Xie, Dawang Zhou, Xianming Deng, Hong-Lin Chan, Tong-Jin Zhao () and Hong-Rui Wang ()
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Mingdong Liu: Xiamen University
Taoling Zeng: Xiamen University
Xin Zhang: Xiamen University
Chunyan Liu: Xiamen University
Zhihui Wu: Xiamen University
Luming Yao: Xiamen University
Changchuan Xie: Xiamen University
Hui Xia: Xiamen University
Qi Lin: Xiamen University
Liping Xie: Xiamen University
Dawang Zhou: Xiamen University
Xianming Deng: Xiamen University
Hong-Lin Chan: National Tsing Hua University
Tong-Jin Zhao: Xiamen University
Hong-Rui Wang: Xiamen University

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: Abstract DNA damage can induce autophagy; however, the underlying mechanism remains largely unknown. Here we report that DNA damage leads to autophagy through ATR/Chk1/RhoB-mediated lysosomal recruitment of TSC complex and subsequent mTORC1 inhibition. DNA damage caused by ultraviolet light (UV) or alkylating agent methyl methanesulphonate (MMS) results in phosphorylation of small GTPase RhoB by Chk1. Phosphorylation of RhoB enhances its interaction with the TSC2, and promotes its sumoylation by PIAS1, which is required for RhoB/TSC complex to translocate to lysosomes. As a result, mTORC1 is inhibited, and autophagy is activated. Knockout of RhoB severely attenuates lysosomal translocation of TSC complex and the DNA damage-induced autophagy. Reintroducing wild-type but not sumoylation-resistant RhoB into RhoB−/− cells restores the onset of autophagy. Hence, our study identifies a molecular mechanism for translocation of TSC complex to lysosomes in response to DNA damage, which depends on ATR/Chk1-mediated RhoB phosphorylation and sumoylation.

Date: 2018
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DOI: 10.1038/s41467-018-06556-9

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