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

Zhenhua Xu, Yiwen Bu, Nilesh Chitnis, Costas Koumenis, Serge Y. Fuchs and J. Alan Diehl ()
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Zhenhua Xu: Hollings Cancer Center, Medical University of South Carolina
Yiwen Bu: Hollings Cancer Center, Medical University of South Carolina
Nilesh Chitnis: Hollings Cancer Center, Medical University of South Carolina
Costas Koumenis: Perelman School of Medicine, University of Pennsylvania
Serge Y. Fuchs: School of Veterinary Medicine, 380 S. University Avenue
J. Alan Diehl: Hollings Cancer Center, Medical University of South Carolina

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: Abstract 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.

Date: 2016
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DOI: 10.1038/ncomms11422

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