Department of Biochemistry, Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, 3400, Charleston, South Carolina 29425, USA.
Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Nat Commun. 2016 May 13;7:11422. 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.
未折叠蛋白反应（UPR）通过基因表达和蛋白质合成来调节细胞内稳态的能力已有充分的文献记载。一种对 PERK 和 Ire1 信号都有反应的主要促凋亡蛋白是 CHOP/GADD153 转录因子。虽然 CHOP 缺失会延迟细胞死亡的发生，但关于 CHOP 如何调节细胞凋亡仍存在一些问题。在这里，我们提供的证据表明，CHOP/GADD153 依赖性细胞凋亡反映了 micro-RNA，miR-216b 的表达。miR-216b 的积累需要 PERK 依赖性诱导的 CHOP/GADD153，而 CHOP/GADD153 则直接调节 miR-216b 的表达。由于 miR-216b 的最大表达受到 Ire1 的拮抗，因此 miR-216b 的积累反映了 PERK 和 Ire1 活性的收敛。从功能上讲，miR-216b 直接靶向 c-Jun，从而降低了 AP-1 依赖性转录，并使细胞对 ER 应激依赖性凋亡敏感。这些结果为 CHOP/GADD153 依赖性细胞死亡的分子机制提供了直接的见解。
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