TY - JOUR 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 PY - 2022 TI - TFEB, a master regulator of autophagy and biogenesis, unexpectedly promotes apoptosis in response to the cyclopentenone prostaglandin 15d-PGJ2 JF - Acta Pharmacologica Sinica; Vol 43, No 5 (May 2022): Acta Pharmacologica Sinica Y2 - 2022 KW - 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-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. UR - http://www.chinaphar.com/article/view/10563