BACKGROUND Myriad challenges to the proper folding and structural maturation of secretory pathway client proteins in the endoplasmic reticulum (ER) - a condition referred to as "ER stress" - activate intracellular signaling pathways termed the unfolded protein response (UPR). SCOPE OF REVIEW Through executing transcriptional and translational programs the UPR restores homeostasis in those cells experiencing manageable levels of ER stress. But the UPR also actively triggers cell degeneration and apoptosis in those cells that are encountering ER stress levels that exceed irremediable thresholds. Thus, UPR outputs are "double-edged". In pancreatic islet β-cells, numerous genetic mutations affecting the balance between these opposing UPR functions cause diabetes mellitus in both rodents and humans, amply demonstrating the principle that the UPR is critical for the proper functioning and survival of the cell. MAJOR CONCLUSIONS Specifically, we have found that the UPR master regulator IRE1α kinase/endoribonuclease (RNase) triggers apoptosis, β-cell degeneration, and diabetes, when ER stress reaches critical levels. Based on these mechanistic findings, we find that novel small molecule compounds that inhibit IRE1α during such "terminal" UPR signaling can spare ER stressed β-cells from death, perhaps affording future opportunities to test new drug candidates for disease modification in patients suffering from diabetes.

中文翻译：

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内质网应激，胰腺胰岛β细胞变性以及糖尿病中未折叠蛋白应答的治疗性调节。

背景技术对内质网（ER）中的分泌途径客户蛋白的适当折叠和结构成熟的无数挑战-一种被称为“ ER应激”的条件-激活了被称为未折叠蛋白应答（UPR）的细胞内信号传导途径。审查范围通过执行转录和翻译程序，UPR可恢复处于可控制水平的ER应激的细胞中的体内平衡。但是，UPR还会在遇到超过不可修复阈值的ER应激水平的细胞中主动触发细胞变性和凋亡。因此，UPR输出为“双刃”。在胰腺胰岛β细胞中，影响这些相反的UPR功能之间平衡的众多遗传突变会导致啮齿动物和人类患上糖尿病，充分证明了UPR对于细胞的正常功能和存活至关重要。主要结论具体来说，我们发现当ER应激达到临界水平时，UPR主调节剂IRE1α激酶/核糖核酸内切酶（RNase）触发凋亡，β细胞变性和糖尿病。基于这些机制的发现，我们发现在这种“终末” UPR信号传导期间抑制IRE1α的新型小分子化合物可以使ER应激的β细胞免于死亡，也许为将来在糖尿病患者中测试候选药物治疗疾病的机会。ER压力达到临界水平时，β细胞变性和糖尿病。基于这些机制的发现，我们发现在这种“终末” UPR信号传导期间抑制IRE1α的新型小分子化合物可以使ER应激的β细胞免于死亡，也许为将来在糖尿病患者中测试候选药物治疗疾病的机会。ER压力达到临界水平时，β细胞变性和糖尿病。基于这些机制的发现，我们发现在这种“终末” UPR信号传导期间抑制IRE1α的新型小分子化合物可以使ER应激的β细胞免于死亡，也许为将来在糖尿病患者中测试候选药物治疗疾病的机会。