Wolfram syndrome 1 gene regulates pathways maintaining beta cell health and survival
| Autor: | David W. Piston, Fumihiko Urano, John M P Revilla, Kelly Kries, Rie Asada, Damien Abreu, Zeno Lavagnino |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
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 |
| Zdroj: | Laboratory investigation; a journal of technical methods and pathology |
| ISSN: | 1530-0307 0023-6837 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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