首页|XBP1 splicing contributes to endoplasmic reticulum stress-induced human islet amyloid polypeptide up-regulation

XBP1 splicing contributes to endoplasmic reticulum stress-induced human islet amyloid polypeptide up-regulation

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As a pathological hallmark of type 2 diabetes mellitus(T2DM),islet amyloid is formed by the aggregation of islet amyloid polypeptide(IAPP).Endoplasmic reticulum(ER)stress interacts with IAPP aggregates and has been implicated in the pathogenesis of T2DM.To examine the role of ER stress in T2DM,we cloned the hIAPP promoter and analyzed its pro-moter activity in human β-cells.We found that ER stress significantly enhanced hIAPP promoter activity and expression in human β-cells via triggering X-box binding protein 1(XBP1)splicing.We identified a binding site of XBP1 in the hIAPP promoter.Disruption of this binding site by substitution or deletion mutagenesis significantly diminished the effects of ER stress on hIAPP promoter activity.Blockade of XBP splicing by MKC3946 treatment inhibited ER stress-induced hIAPP up-regulation and improved human β-cell survival and function.Our study uncovers a link between ER stress and IAPP at the transcriptional level and may provide novel insights into the role of ER stress in IAPP cytotoxicity and the pathogenesis of T2DM.

β-cell functionEndoplasmic reticulum stressIslet amyloid polypeptideType 2 diabetes mellitusXBP1

Yun Zhang、Susan Lin、Jing Yao、Wantong Cai、Huaqiu Chen、Ailikemu Aierken、Zhe Wang、Weihong Song

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National Clinical Research Center for Geriatric Disorders,Xuanwu Hospital,Capital Medical University,Beijing 100053,China

Townsend Family Laboratories,Department of Psychiatry,The University of British Columbia,2255 Wesbrook Mall,Vancouver,BC V6T 1Z3,Canada

Institute of Aging,Key Laboratory of Alzheimer's Disease of Zhejiang Province,School of Mental Health and the Affiliated Kangning Hospital,Wenzhou Medical University,Wenzhou,Zhejiang 325000,China

Oujiang Laboratory(Zhejiang Lab for Regenerative Medicine,Vision and Brain Health),Wenzhou,Zhejiang 325001,China

Oujiang Laboratory(Zhejiang Lab for Regenerative Medicine

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National Natural Science Foundation of ChinaBeijing Hospitals Authority Youth Programme(China)Beijing Medical Research 2021-8,Key Laboratory of Alzheimer's Disease of Zhejiang Province of ChinaNational Natural Science Foundation of China

82201576QML20210804ZJAD-202100482230043

2024

10.1016/j.gendis.2023.101148

基因与疾病(英文)

基因与疾病(英文)

ISSN：
年,卷(期)：2024.11(5)