Article

TFEB, a master regulator of autophagy and biogenesis, unexpectedly promotes apoptosis in response to the cyclopentenone prostaglandin 15d-PGJ2

Chuan-bin Yang1,2,3, Jia Liu3, Benjamin Chun-Kit Tong3, Zi-ying Wang3,4, Zhou Zhu3, Cheng-fu Su3, Sravan Gopalkrishnashetty Sreenivasmurthy3, Jia-xi Wu3, Ashok Iyaswamy3, Senthilkumar Krishnamoorthi3, Shi-ying Huang1,2, King-ho Cheung3, Ju-xian Song3,5, Jie-qiong Tan6, Jia-hong Lu7, Min Li3
1 Department of Geriatrics, Shenzhen People’s Hospital, (The Second Clinical Medical College, Jinan University
2 The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, China
3 Mr. and Mrs. Ko Chi Ming Centre for Parkinson’s Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
4 Interdisciplinary Institute for Personalized Medicine in Brain Disorders, Jinan University, Guangzhou 510632, China
5 Medical College of Acupuncture-Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
6 Center for Medical Genetics and Hunan Key Laboratory of Animal Model for Human Diseases, School of Life Sciences, Central South University, Changsha 410006, China
7 State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau SAR, China
Correspondence to: Min Li: limin@hkbu.edu.hk,
DOI: 10.1038/s41401-021-00711-7
Received: 5 October 2020
Accepted: 1 June 2021
Advance online: 20 August 2021

Abstract

Transcriptional factor EB (TFEB), a master regulator of autophagy and lysosomal biogenesis, is generally regarded as a pro-survival factor. Here, we identify that besides its effect on autophagy induction, TFEB exerts a pro-apoptotic effect in response to the cyclopentenone prostaglandin 15-deoxy-Δ-12,14-prostaglandin J2 (15d-PGJ2). Specifically, 15d-PGJ2 promotes TFEB translocation from the cytoplasm into the nucleus to induce autophagy and lysosome biogenesis via reactive oxygen species (ROS) production rather than mTORC1 inactivation. Surprisingly, TFEB promotes rather than inhibits apoptosis in response to 15d-PGJ2. Mechanistically, ROS-mediated TFEB translocation into the nucleus transcriptionally upregulates the expression of ATF4, which is required for apoptosis elicited by 15d-PGJ2. Additionally, inhibition of TFEB activation by ROS scavenger N-acetyl cysteine or inhibition of protein synthesis by cycloheximide effectively compromises ATF4 upregulation and apoptosis in response to 15d- PGJ2. Collectively, these results indicate that ROS-induced TFEB activation exerts a novel role in promoting apoptosis besides its role in regulating autophagy in response to 15d-PGJ2. This work not only evidences how TFEB is activated by 15d-PGJ2, but also unveils a previously unexplored role of ROS-dependent activation of TFEB in modulating cell apoptosis in response to 15d-PGJ2.
Keywords: transcriptional factor EB (TFEB); 15-deoxy-Δ-12 14-prostaglandin J2 (15d-PGJ2); autophagy and lysosome biogenesis; ATF4; ER stress; apoptosis

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