The IRE1α-XBP1 pathway regulates metabolic stressinduced compensatory proliferation of pancreatic β-cells

• Published in: 细胞研究：英文版 2014 (9), p.1137-1140
• Main Author: Tongfu Xu Liu Yang Cheng Yan Xiaoxia Wang Ping Huang Feng Zhao Liyun Zhao Mingliang Zhang Weiping Jia Xiangdong Wang Yong Liu
• Format: Article
• Language: English
• Subjects: 丝氨酸/苏氨酸蛋白激酶; 代谢; 内质网应激; 核酸内切酶; 细胞功能; 胰岛素分泌; 胰腺; 蛋白质折叠
• ISSN: 1001-0602; 1748-7838

Dear Editor, 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 （IRE 1）, 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 IRE 1 α results in non-conventional splicing of the mRNA encoding the transcription factor X-box binding protein 1 （XBP 1）, generating a spliced active form of XBP1 （XBPls） to initiate a major UPR program [1]. The IRE1-XBP1 path- way has been implicated in the homeostatic regulation of pancreatic islet β-cells. Whereas glucose-stimulated IREla activation is coupled to insulin production [5-7], IRE 1α 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 IRE 1α in integrating metabolic ER stress signals to regulate β-cell functions remains largely elusive.