| First Author | Abreu D | Year | 2020 |
| Journal | Lab Invest | Volume | 100 |
| Issue | 6 | Pages | 849-862 |
| PubMed ID | 32060407 | Mgi Jnum | J:297190 |
| Mgi Id | MGI:6472016 | Doi | 10.1038/s41374-020-0408-5 |
| Citation | Abreu D, et al. (2020) Wolfram syndrome 1 gene regulates pathways maintaining beta-cell health and survival. Lab Invest 100(6):849-862 |
| abstractText | 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 beta-cell outcomes secondary to WFS1 function, however, remain unclear. Here, we show that WFS1 preserves normal beta-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 beta-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 beta-cell pathology. Taken together, this work reveals essential pathways regulated by WFS1 to control beta-cell survival and function primarily through preservation of ER homeostasis. |
