Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, MO, 63110, USA.
Medical Scientist Training Program, Washington University School of Medicine, St. Louis, MO, 63110, USA.
Lab Invest. 2020 Jun;100(6):849-862. doi: 10.1038/s41374-020-0408-5. Epub 2020 Feb 14.
Wolfram Syndrome 1 (WFS1) protein is an endoplasmic reticulum (ER) factor whose deficiency results in juvenile-onset diabetes secondary to cellular dysfunction and apoptosis. The mechanisms guiding β-cell outcomes secondary to WFS1 function, however, remain unclear. Here, we show that WFS1 preserves normal β-cell physiology by promoting insulin biosynthesis and negatively regulating ER stress. Depletion of Wfs1 in vivo and in vitro causes functional defects in glucose-stimulated insulin secretion and insulin content, triggering Chop-mediated apoptotic pathways. Genetic proof of concept studies coupled with RNA-seq reveal that increasing WFS1 confers a functional and a survival advantage to β-cells under ER stress by increasing insulin gene expression and downregulating the Chop-Trib3 axis, thereby activating Akt pathways. Remarkably, WFS1 and INS levels are reduced in type-2 diabetic (T2DM) islets, suggesting that WFS1 may contribute to T2DM β-cell pathology. Taken together, this work reveals essential pathways regulated by WFS1 to control β-cell survival and function primarily through preservation of ER homeostasis.
沃尔夫拉森综合征 1（WFS1）蛋白是内质网（ER）的一种因子，其缺乏会导致细胞功能障碍和细胞凋亡引起的青少年发病型糖尿病。然而，指导 WFS1 功能导致β细胞结果的机制尚不清楚。在这里，我们表明 WFS1 通过促进胰岛素生物合成和负调控内质网应激来维持正常的β细胞生理学。体内和体外敲除 Wfs1 会导致葡萄糖刺激的胰岛素分泌和胰岛素含量的功能缺陷，引发 Chop 介导的凋亡途径。遗传概念验证研究与 RNA-seq 相结合揭示，增加 WFS1 通过增加胰岛素基因表达和下调 Chop-Trib3 轴，从而激活 Akt 途径，赋予β细胞在 ER 应激下的功能和存活优势。值得注意的是，2 型糖尿病（T2DM）胰岛中的 WFS1 和 INS 水平降低，表明 WFS1 可能导致 T2DM β 细胞病理学。总之，这项工作揭示了 WFS1 调节的重要途径，主要通过维持内质网稳态来控制β细胞的存活和功能。
