miR-216b regulation of c-Jun mediates GADD153/CHOP-dependent apoptosis

• Published in: Nature communications 2016-05, Vol.7 (1), p.11422-11422, Article 11422
• Main Authors: Xu, Zhenhua, Bu, Yiwen, Chitnis, Nilesh, Koumenis, Costas, Fuchs, Serge Y., Diehl, J. Alan
• Format: Article
• Language: English
• Subjects: 13; 13/109; 13/2; 13/31; 13/95; 631/337/384/331; 631/45/612/822; 631/80/82/23; 631/80/86; 96; 96/95; Animals; Apoptosis; Cell death; Cell Line; Cell Line, Tumor; Cell Survival; eIF-2 Kinase - genetics; eIF-2 Kinase - metabolism; Endoplasmic Reticulum Stress; Endoribonucleases - genetics; Endoribonucleases - metabolism; Gene expression; Homeostasis; Humanities and Social Sciences; Humans; Kinases; Mice; MicroRNAs - genetics; MicroRNAs - metabolism; multidisciplinary; Protein expression; Protein folding; Protein synthesis; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins c-jun - genetics; Proto-Oncogene Proteins c-jun - metabolism; Science; Science (multidisciplinary); Transcription Factor CHOP - genetics; Transcription Factor CHOP - metabolism; Transcription factors; Unfolded Protein Response
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms11422

The ability of the unfolded protein response, UPR, to regulate cell homeostasis through both gene expression and protein synthesis has been well documented. One primary pro-apoptotic protein that responds to both PERK and Ire1 signalling is the CHOP/GADD153 transcription factor. Although CHOP deficiency delays onset of cell death, questions remain regarding how CHOP regulates apoptosis. Here, we provide evidence demonstrating that CHOP/GADD153-dependent apoptosis reflects expression of micro-RNA, miR-216b. MiR-216b accumulation requires PERK-dependent induction of CHOP/GADD153, which then directly regulates miR-216b expression. As maximal expression of miR-216b is antagonized by Ire1, miR-216b accumulation reflects the convergence of PERK and Ire1 activities. Functionally, miR-216b directly targets c-Jun, thereby reducing AP-1-dependent transcription and sensitizing cells to ER stress-dependent apoptosis. These results provide direct insight into the molecular mechanisms of CHOP/GADD153-dependent cell death. The transcription factor CHOP/GADD153 regulates apoptosis in response to the unfolded protein response. Here the authors show that CHOP/GADD153 regulates the expression of miR-216b, which targets c-Jun and sensitizes cells to ER stress-dependent apoptosis.