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

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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

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-∆-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.

Original languageEnglish
Pages (from-to)1251–1263
Number of pages13
JournalActa Pharmacologica Sinica
Volume43
Issue number5
Early online date20 Aug 2021
DOIs
Publication statusPublished - May 2022

Scopus Subject Areas

  • Pharmacology
  • Pharmacology (medical)

User-Defined Keywords

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

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