1. Wolfram syndrome 1 gene regulates pathways maintaining beta cell health and survival
- Author
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David W. Piston, Fumihiko Urano, John M P Revilla, Kelly Kries, Rie Asada, Damien Abreu, and Zeno Lavagnino
- Subjects
0301 basic medicine ,Blood Glucose ,endocrine system ,endocrine system diseases ,Wolfram syndrome ,medicine.medical_treatment ,Biology ,Article ,Pathology and Forensic Medicine ,Cell Line ,03 medical and health sciences ,0302 clinical medicine ,Insulin-Secreting Cells ,Gene expression ,medicine ,Animals ,Humans ,Insulin ,Molecular Biology ,Protein kinase B ,Cells, Cultured ,Mice, Knockout ,Endoplasmic reticulum ,nutritional and metabolic diseases ,Membrane Proteins ,Wolfram Syndrome ,Cell Biology ,medicine.disease ,Endoplasmic Reticulum Stress ,Cell biology ,030104 developmental biology ,030220 oncology & carcinogenesis ,Unfolded protein response ,Beta cell ,Homeostasis ,Signal Transduction - Abstract
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., Summary Urano WFS1 is a causative gene for Wolfram syndrome, a rare neurodegenerative disorder characterized by juvenile-onset diabetes mellitus and optic nerve atrophy. Genetic proof of concept studies coupled with RNA-seq reveal that increasing WFS1 confers a survival advantage to cells under ER stress by activating Akt pathways and preserving ER homeostasis. This work reveals essential pathways regulated by WFS1 and therapeutic targets for Wolfram syndrome.
- Published
- 2020