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

作　　者：Chuan-bin Yang Jia Liu Benjamin Chun-Kit Tong Zi-ying Wang Zhou Zhu Cheng-fu Su Sravan Gopalkrishnashetty Sreenivasmurthy Jia-xi Wu Ashok Iyaswamy Senthilkumar Krishnamoorthi Shi-ying Huang King-ho Cheung Ju-xian Song Jie-qiong Tan Jia-hong Lu Min Li 

机构地区：[1]Department of Geriatrics,Shenzhen People’s Hospital,(The Second Clinical Medical College,Jinan University,The First Affiliated Hospital,Southern University of Science and Technology),Shenzhen,518020,China [2]Mr.and Mrs.Ko Chi Ming Centre for Parkinson’s Disease Research,School of Chinese Medicine,Hong Kong Baptist University,Hong Kong SAR,China [3]Interdisciplinary Institute for Personalized Medicine in Brain Disorders,Jinan University,Guangzhou,510632,China [4]Medical College of Acupuncture-Moxibustion and Rehabilitation,Guangzhou University of Chinese Medicine,Guangzhou,510006,China [5]Center for Medical Genetics and Hunan Key Laboratory of Animal Model for Human Diseases,School of Life Sciences,Central South University,Changsha,410006,China [6]State Key Laboratory of Quality Research in Chinese Medicine,Institute of Chinese Medical Sciences,University of Macao,Macao SAR,China

出　　处：《Acta Pharmacologica Sinica》2022年第5期1251-1263,共13页中国药理学报（英文版）

基　　金：We would like to thank Prof.Richard J.Youle(US National Institute of Neurological Disorders and Stroke)and Prof.Myung-Shik Lee(Yonsei University College of Medicine)for providing TFEB knockout HeLa cells.We thank Martha Dahlen for the English editing.This study was supported by the Hong Kong General Research Fund(GRF/HKBU12101417,GRF/HKBU12100618);the National Natural Science Foundation of China(81703487,and 81773926);Shenzhen Science and Technology Innovation Commission(JCYJ20180302174028790,JCYJ20180507184656626);the Hong Kong Health and Medical Research Fund(HMRF17182541,HMRF17182551);research funds from Hong Kong Baptist University(HKBU/RC-IRCs/17-18/03).

摘　　要：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-∆-^(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.

关 键 词：transcriptional factor EB(TFEB) 15-deoxy-∆-12 14-prostaglandin J2(15d-PGJ2) autophagy and lysosome biogenesis ATF4 ER stress apoptosis 

分 类 号：R363[医药卫生—病理学]