TY - JOUR
T1 - TFEB, a master regulator of autophagy and biogenesis, unexpectedly promotes apoptosis in response to the cyclopentenone prostaglandin 15d-PGJ2
AU - Yang, Chuan Bin
AU - Liu, Jia
AU - Tong, Benjamin Chun Kit
AU - Wang, Zi Ying
AU - Zhu, Zhou
AU - Su, Cheng Fu
AU - Sreenivasmurthy, Sravan Gopalkrishnashetty
AU - Wu, Jia Xi
AU - Iyaswamy, Ashok
AU - Krishnamoorthi, Senthilkumar
AU - Huang, Shi Ying
AU - Cheung, King Ho
AU - Song, Ju Xian
AU - Tan, Jie Qiong
AU - Lu, Jia Hong
AU - Li, Min
N1 - Funding Information:
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), and research funds from Hong Kong Baptist University (HKBU/RC-IRCs/17-18/03).
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to CPS and SIMM
PY - 2022/5
Y1 - 2022/5
N2 - 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.
AB - 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.
KW - 15-deoxy-∆-12,14-prostaglandin J2 (15d-PGJ2)
KW - apoptosis
KW - ATF4
KW - autophagy and lysosome biogenesis
KW - ER stress
KW - transcriptional factor EB (TFEB)
UR - http://www.scopus.com/inward/record.url?scp=85113242010&partnerID=8YFLogxK
U2 - 10.1038/s41401-021-00711-7
DO - 10.1038/s41401-021-00711-7
M3 - Journal article
AN - SCOPUS:85113242010
SN - 1671-4083
VL - 43
SP - 1251
EP - 1263
JO - Acta Pharmacologica Sinica
JF - Acta Pharmacologica Sinica
IS - 5
ER -