The apoptosis inhibitor ARC alleviates the ER stress response to promote β-cell survival.
The apoptosis inhibitor ARC alleviates the ER stress response to promote β-cell survival.
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作者：
McKimpson WM;Weinberger J;Czerski L;Zheng M;Crow MT;Pessin JE;Chua SC Jr;Kitsis RN
2型糖尿病涉及胰岛素抵抗和β细胞衰竭，导致胰岛素分泌不足。细胞衰竭的一个重要组成部分是细胞凋亡引起的细胞损失。具有半胱天冬酶募集结构域的凋亡抑制因子（Apoptosis repressor with caspase recruitment domain，ARC）是一种在心肌和骨骼肌细胞及神经元中表达的凋亡抑制因子。ARC具有拮抗外源性（死亡受体）和内源性（线粒体/内质网[ER]）细胞死亡途径的不寻常特性。在这里，我们报告ARC蛋白在内分泌胰腺细胞中丰富，包括>99.5%的小鼠和73%的人β细胞。使用遗传功能获得和丧失方法，我们的数据表明ARC抑制多种细胞死亡诱导剂引起的β细胞凋亡，包括ER应激源衣霉素、毒胡萝卜素和生理浓度的棕榈酸酯。出乎意料的是，ARC减少了ER应激反应，作用于蛋白激酶RNA样ER激酶（PERK）和肌醇需要蛋白1α的远端，以抑制C/EBP同源蛋白（CHOP）的诱导。在分离的胰岛中ARC的消耗增强棕榈酸诱导的细胞凋亡，这是显着地通过删除CHOP拯救。这些数据表明，ARC是一种以前未被认识到的β细胞凋亡抑制剂，其保护作用是通过抑制ER应激反应途径介导的。
Type 2 diabetes involves insulin resistance and β-cell failure leading to inadequate insulin secretion. An important component of β-cell failure is cell loss by apoptosis. Apoptosis repressor with caspase recruitment domain (ARC) is an inhibitor of apoptosis that is expressed in cardiac and skeletal myocytes and neurons. ARC possesses the unusual property of antagonizing both the extrinsic (death receptor) and intrinsic (mitochondria/endoplasmic reticulum [ER]) cell death pathways. Here we report that ARC protein is abundant in cells of the endocrine pancreas, including >99.5% of mouse and 73% of human β-cells. Using genetic gain- and loss-of-function approaches, our data demonstrate that ARC inhibits β-cell apoptosis elicited by multiple inducers of cell death, including ER stressors tunicamycin, thapsigargin, and physiological concentrations of palmitate. Unexpectedly, ARC diminishes the ER stress response, acting distal to protein kinase RNA-like ER kinase (PERK) and inositol-requiring protein 1α, to suppress C/EBP homologous protein (CHOP) induction. Depletion of ARC in isolated islets augments palmitate-induced apoptosis, which is dramatically rescued by deletion of CHOP. These data demonstrate that ARC is a previously unrecognized inhibitor of apoptosis in β-cells and that its protective effects are mediated through suppression of the ER stress response pathway.
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