Wolfram syndrome 1 gene regulates pathways maintaining beta-cell health and survival

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.

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Fig. 1: Glucose tolerance and β-cell morphometry in whole body WFS1–/– 129S6 mice.
Fig. 2: WFS1 positively regulates insulin biosynthesis and β-cell maturity markers.
Fig. 3: WFS1 overexpression suppresses ER stress-mediated cell death.
Fig. 4: WFS1 knockdown promotes β-cell dysfunction, ER stress, and β-cell death.
Fig. 5: WFS1 expression is decreased in type-2 diabetic human donor islets.

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Acknowledgements

We thank the Genome Technology Access Center in the Department of Genetics at Washington University School of Medicine for help with genomic analysis. The Center is partially supported by NCI Cancer Center Support Grant P30CA91842 to the Siteman Cancer Center and by ICTS/CTSA Grant UL1TR000448 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. This publication is solely the responsibility of the authors and does not necessarily represent the official view of NCRR or NIH. The authors would like to acknowledge Cris Brown, Akari Takesato, and Lucas Peng for their technical assistance. This work was partly supported by the grants from the National Institutes of Health/NIDDK (DK112921, DK020579) and National Institutes of Health/NCATS (TR002065, TR000448) and philanthropic supports from the Unravel Wolfram Syndrome Fund, the Feiock Fund, the Silberman Fund, the Stowe Fund, the Ellie White Foundation for Rare Genetic Disorders, the Eye Hope Foundation, and the Snow Foundation to FU, DA was supported by the NIH training grant (F30DK111070).

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Correspondence to Fumihiko Urano.

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Abreu, D., Asada, R., Revilla, J.M.P. et al. Wolfram syndrome 1 gene regulates pathways maintaining beta-cell health and survival. Lab Invest (2020). https://doi.org/10.1038/s41374-020-0408-5

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