ER stress and the decline and fall of pancreatic beta cells in type 1 diabetes.
ER stress and the decline and fall of pancreatic beta cells in type 1 diabetes.
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DOI：
10.3109/03009734.2015.1135217
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发表时间：
2016-05
影响因子：
3.4
通讯作者：
Eizirik DL
中科院分区：
文献类型：
--
作者：
Brozzi F;Eizirik DL
未折叠蛋白反应(UPR)的组成部分调节早期1型糖尿病(T1D)的β细胞炎症和死亡。UPR是细胞对错误折叠的蛋白质在内质网(ER)中堆积做出反应的一种机制。它的目的是恢复细胞内稳态，但在慢性或压倒性内质网应激的情况下，UPR的持续激活会触发细胞凋亡，导致T1D和2型糖尿病患者β细胞的丧失。从生理性的UPR到病理性的UPR的转变是如何以及为什么发生的，还有待确定。UPR的一个关键成分是内质网跨膜蛋白IRE1α(肌醇需要酶1α)。IRE1的α活性既受内质网内信号的调节，也受其胞浆结构域形成的蛋白质复合体的调节。IRE1JNK信号的幅度和持续时间对于适应性程序和细胞死亡程序之间的转换至关重要，尤其与β细胞中促凋亡的c-jun氨基末端激酶(α)的激活有关。在本综述中，我们讨论了β细胞中IRE1UPR调节蛋白及其下游靶点的现有信息，以及细胞因子诱导的人和啮齿动物β细胞中α的重要差异。
Components of the unfolded protein response (UPR) modulate beta cell inflammation and death in early type 1 diabetes (T1D). The UPR is a mechanism by which cells react to the accumulation of misfolded proteins in the endoplasmic reticulum (ER). It aims to restore cellular homeostasis, but in case of chronic or overwhelming ER stress the persistent activation of the UPR triggers apoptosis, contributing to the loss of beta cells in both T1D and type 2 diabetes. It remains to be determined how and why the transition from ‘physiological’ to ‘pathological’ UPR takes place. A key component of the UPR is the ER transmembrane protein IRE1α (inositol-requiring enzyme 1α). IRE1α activity is modulated by both intra-ER signals and by the formation of protein complexes at its cytosolic domain. The amplitude and duration of IRE1α signaling is critical for the transition between the adaptive and cell death programs, with particular relevance for the activation of the pro-apoptotic c-Jun N-terminal kinase (JNK) in beta cells. In the present review we discuss the available information on IRE1α-regulating proteins in beta cells and their downstream targets, and the important differences observed between cytokine-induced UPR in human and rodent beta cells.