The IRE1α-XBP1 pathway regulates metabolic stressinduced compensatory proliferation of pancreatic β-cells
The IRE1α-XBP1 pathway regulates metabolic stressinduced compensatory proliferation of pancreatic β-cells
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IRE1α-XBP1 途径调节代谢应激诱导的胰腺 β 细胞的代偿性增殖
DOI：
10.1038/cr.2014.55
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发表时间：
2014
期刊：
影响因子：
44.1
通讯作者：
Yong Liu
中科院分区：
文献类型：
--
作者：
Tongfu Xu;Liu Yang;Cheng Yan;Xiaoxia Wang;Ping Huang;Feng Zhao;Liyun Zhao;Mingliang Zhang;Weiping Jia;Xiangdong Wang;Yong Liu
在真核生物中，内质网(ER)上蛋白质折叠需求的增加激活了未折叠蛋白反应(UPR)[1]，UPR在控制细胞功能和内质网应激下的生存中起着关键作用[2]。慢性内质网应激被认为有助于糖尿病的致病进展[3，4]。肌醇需求酶1(IRE1)是一种内质网驻留的跨膜丝氨酸/苏氨酸蛋白激酶和内切核酸酶，是最保守的内质网应激感受器，介导着UPR的一个关键分支[1]。在哺乳动物中，IRE1mRNA的激活导致编码转录因子X盒结合蛋白1(XBP1)的α的非常规剪接，产生XBP1的剪接活性形式(XBP1s)来启动主要的UPR计划[1]。IRE1-XBP1通路参与了胰岛β-细胞的动态平衡调节。虽然葡萄糖刺激的IRE1mRNAs激活与胰岛素的产生有关[5-7]，但在严重的内质网应激条件下，IRE1mRNAs也会降解胰岛素α[8]。有趣的是，据报道，小鼠β细胞中XBP1的基因缺失会导致IRE1α的反馈过度激活，导致胰岛素原加工和胰岛素分泌缺陷[9]。然而，Ire 1α在体内整合代谢内质网应激信号以调节β细胞功能方面的确切作用仍不清楚。为了研究Ire 1α在β细胞中的代谢作用，我们将Ire 1αf/f小鼠[10]与在大鼠胰岛素II启动子控制下表达Cre重组酶的转基因小鼠杂交，获得了α细胞特异性Ire 1β缺失的小鼠(记为Ire 1αf/f：Cre)。由于野生型和Cre胎之间的体重和喂养血糖水平没有显著差异(补充信息，图S1a)，所以我们使用Cre和Ire 1αf/f小鼠作为对照。与Ire 1αf/f：Cre小鼠相比，Ire 1α蛋白在初级胰岛(~75%)和下丘脑(~50%)中显著降低，而在肝脏中没有观察到明显的变化(补充
In eukaryotes, increased protein folding demand at the endoplasmic reticulum (ER) activates the unfolded protein response (UPR)[1], which plays a pivotal role in control of cellular functions and survival under ER stress [2]. Chronic ER stress is thought to contribute to the pathogenic progression of diabetes [3, 4]. Inositol-requiring enzyme 1 (IRE1), an ER-resident transmembrane Ser/Thr protein kinase and endoribonuclease, is the most conserved ER stress sensor that mediates a key branch of the UPR [1]. In mammals, activation of IRE1α results in non-conventional splicing of the mRNA encoding the transcription factor X-box binding protein 1 (XBP1), generating a spliced active form of XBP1 (XBP1s) to initiate a major UPR program [1]. The IRE1-XBP1 pathway has been implicated in the homeostatic regulation of pancreatic islet β-cells. Whereas glucose-stimulated IRE1α activation is coupled to insulin production [5-7], IRE1α also degrades insulin mRNAs under severe ER stress conditions [8]. Interestingly, genetic deletion of XBP1 in β-cells of mice was reported to result in a feedback hyperactivation of IRE1α, causing defective proinsulin processing and insulin secretion [9]. However, the precise role in vivo of IRE1α in integrating metabolic ER stress signals to regulate β-cell functions remains largely elusive.To investigate the metabolic actions of IRE1α in β-cells, we generated mice (denoted Ire1αf/f: Cre) with specific Ire1α deletion in β-cells by intercrossing Ire1αf/f mice [10] with RIP-Cre transgenic mice (denoted Cre) that express Cre recombinase under the control of the rat insulin II promoter. Because no significant differences were observed in body weight and fed blood glucose levels between wild-type and Cre littermates (Supplementary information, Figure S1A), we used Cre and Ire1αf/f mice as the control. In Ire1αf/f: Cre mice, IRE1α protein levels were substantially decreased in primary islets (by~ 75%) and hypothalamus (by~ 50%) as compared to their Ire1αf/f: Cre or Cre counterparts, while no distinguishable changes were observed in their livers (Supplementary