An important event in the unfolded protein response (UPR) is the activation of the endoplasmic reticulum kinase PERK (EIF2AK3). The PERK signalling branch first mediates a prosurvival response, which switches into a proapoptotic response upon prolonged ER stress. However, the molecular mechanisms of PERK-mediated cell death are not well understood. Here we show that expression of the primary miR-17-92 transcript and mature miRNAs belonging to miR-17-92 cluster is decreased during UPR. We found that activity of miR-17-92 promoter reporter was reduced during UPR in a PERK-dependent manner. We show that activity of miR-17-92 promoter is repressed by ectopic expression of ATF4 and NRF2. The promoter deletion analysis and ChIP assays mapped the region responding to UPR-mediated repression to site in the proximal region of the miR-17-92 promoter. Hypericin-mediated photo-oxidative ER damage reduced the expression of miRNAs belonging to miR-17-92 cluster in wild-type but not in PERK-deficient cells. Importantly, ER stress-induced apoptosis was inhibited upon miR-17-92 overexpression in SH-SY5Y and H9c2 cells. Our results reveal a novel function for NRF2, where repression of miR-17-92 cluster by NRF2 plays an important role in ER stress-mediated apoptosis. The data presented here provides mechanistic details how sustained PERK signalling via NRF2 mediated repression of miR-17-92 cluster can potentiate cell death.

中文翻译：

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PERK对miR-17-92簇的下调可微调未折叠的蛋白反应介导的细胞凋亡

展开的蛋白质反应（UPR）中的重要事件是内质网激酶PERK（EIF2AK3）的激活。PERK信号转导分支首先介导了生存应答，当ER压力延长时，它会转变为凋亡应答。但是，PERK介导的细胞死亡的分子机制尚不清楚。在这里，我们显示在普遍定期审议期间，初级miR-17-92转录本和属于miR-17-92簇的成熟miRNA的表达降低了。我们发现，在UPR期间，以PERK依赖性方式降低了miR-17-92启动子报告子的活性。我们表明，miR-17-92启动子的活性被ATF4和NRF2的异位表达所抑制。启动子缺失分析和ChIP分析将对UPR介导的阻抑反应的区域定位在miR-17-92启动子的近端区域。金丝桃素介导的光氧化ER损伤降低了miR-17-92簇中miRNA在野生型中的表达，但在PERK缺陷型细胞中却没有。重要的是，在SH-SY5Y和H9c2细胞中miR-17-92过表达时，ER应激诱导的细胞凋亡受到抑制。我们的结果揭示了NRF2的新功能，其中NRF2抑制miR-17-92簇在内质网应激介导的细胞凋亡中起重要作用。此处提供的数据提供了机械学细节，该信息详细说明了通过NRF2介导的miR-17-92簇阻抑而持续的PERK信号传导如何增强细胞死亡。我们的结果揭示了NRF2的新功能，其中NRF2抑制miR-17-92簇在内质网应激介导的细胞凋亡中起重要作用。此处提供的数据提供了机械学细节，该信息详细说明了通过NRF2介导的miR-17-92簇阻抑而持续的PERK信号传导如何增强细胞死亡。我们的结果揭示了NRF2的新功能，其中NRF2抑制miR-17-92簇在内质网应激介导的细胞凋亡中起重要作用。此处提供的数据提供了机械学细节，该信息详细说明了通过NRF2介导的miR-17-92簇阻抑而持续的PERK信号传导如何增强细胞死亡。