The balance between adaptive and apoptotic unfolded protein responses regulates β-cell death under ER stress conditions through XBP1, CHOP and JNK
The balance between adaptive and apoptotic unfolded protein responses regulates β-cell death under ER stress conditions through XBP1, CHOP and JNK
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DOI：
10.1016/j.mce.2015.06.025
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发表时间：
2015-09-15
影响因子：
4.1
通讯作者：
Laybutt, D. Ross
中科院分区：
文献类型：
--
作者：
Chan, Jeng Yie;Luzuriaga, Jude;Laybutt, D. Ross
内质网（ER）应激和随后的未折叠蛋白反应（UPR）与1型和2型糖尿病的β细胞死亡有关。然而，普遍定期审议也是β细胞适应和生存所需的基本机制。调节UPR从适应性向凋亡性转变的机制尚不清楚。在这里，我们研究了XBP1， CHOP和JNK在1型和2型糖尿病模型中从适应性转变为凋亡性UPR和β细胞死亡之间的关系。XBP1抑制增强了MINE β细胞中由促炎细胞因子或饱和脂肪酸棕榈酸盐诱导的细胞死亡。CHOP抑制阻止了这种反应。IRE1/XBP1抑制导致糖尿病抵抗性ob/ob小鼠的胰岛发生与糖尿病相似的变化，包括细胞死亡、炎症和抗氧化基因表达的增加。同样，IRE1/XBP1抑制增加NOD小鼠胰岛细胞死亡。另一方面，JNK抑制：1)增加糖尿病db/db小鼠胰岛的适应性UPR，减少细胞死亡；2)恢复适应性UPR，同时保护细胞因子暴露后凋亡的UPR基因表达和β细胞死亡和功能障碍。这些发现表明，xbp1介导的适应性和chop依赖的凋亡UPR之间的平衡对于内质网应激下β细胞的存活至关重要。JNK激活调节从适应性到凋亡性UPR的转变，从而提供了1型和2型糖尿病β细胞倾向于细胞死亡而不是内质网应激适应的机制。2015爱思唯尔爱尔兰有限公司版权所有。
Endoplasmic reticulum (ER) stress and the subsequent unfolded protein response (UPR) have been implicated in beta-cell death in type 1 and type 2 diabetes. However, the UPR is also a fundamental mechanism required for beta-cell adaptation and survival. The mechanisms regulating the transition from adaptive to apoptotic UPR remain to be clarified. Here, we investigated the relationships between XBP1, CHOP and JNK in the transition from adaptive to apoptotic UPR and beta-cell death in models of type 1 and type 2 diabetes. XBP1 inhibition potentiated cell death induced by pro-inflammatory cytokines or the saturated fatty acid palmitate in MINE beta-cells. This response was prevented by CHOP inhibition. IRE1/XBP1 inhibition led to alterations in islets from diabetes-resistant ob/ob mice that resemble those found in diabetes, including increases in cell death and inflammation and antioxidant gene expression. Similarly, IRE1/XBP1 inhibition increased cell death in islets from NOD mice. On the other hand, JNK inhibition: 1) increased adaptive UPR and reduced cell death in islets from diabetic db/db mice, and 2) restored adaptive UPR while protecting against apoptotic UPR gene expression and beta-cell death and dysfunction following cytokine exposure. These findings suggest that the balance between XBP1-mediated adaptive and CHOP-dependent apoptotic UPR is critically important for beta-cell survival during ER stress. JNK activation regulates the transition from adaptive to apoptotic UPR, thus providing a mechanism for beta-cell propensity to cell death rather than ER stress adaptation in type 1 and type 2 diabetes. (C) 2015 Elsevier Ireland Ltd. All rights reserved.