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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Cnop M, Welsh N, Jonas JC, Jorns A, Lenzen S, Eizirik DL. Mechanisms of pancreatic beta-cell death in type 1 and type 2 diabetes: many differences, few similarities. Diabetes. 2005;54:S97–107.
Donath MY, Ehses JA, Maedler K, Schumann DM, Ellingsgaard H, Eppler E, et al. Mechanisms of beta-cell death in type 2 diabetes. Diabetes. 2005;54:S108–13.
Back SH, Kaufman RJ. Endoplasmic reticulum stress and type 2 diabetes. Annu Rev Biochem. 2012;81:767–93.
Harding HP, Ron D. Endoplasmic reticulum stress and the development of diabetes: a review. Diabetes. 2002;51:S455–61.
Inoue H, Tanizawa Y, Wasson J, Behn P, Kalidas K, Bernal-Mizrachi E, et al. A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome). Nat Genet. 1998;20:143–8.
Urano F. Wolfram syndrome: diagnosis, management, and treatment. Curr Diabetes Rep. 2016;16:6.
Sandhu MS, Weedon MN, Fawcett KA, Wasson J, Debenham SL, Daly A, et al. Common variants in WFS1 confer risk of type 2 diabetes. Nat Genet. 2007;39:951–3.
Bonnycastle LL, Chines PS, Hara T, Huyghe JR, Swift AJ, Heikinheimo P, et al. Autosomal dominant diabetes arising from a Wolfram syndrome 1 mutation. Diabetes. 2013;62:3943–50.
Fonseca SG, Fukuma M, Lipson KL, Nguyen LX, Allen JR, Oka Y, et al. WFS1 is a novel component of the unfolded protein response and maintains homeostasis of the endoplasmic reticulum in pancreatic beta-cells. J Biol Chem. 2005;280:39609–15.
Fonseca SG, Ishigaki S, Oslowski CM, Lu S, Lipson KL, Ghosh R, et al. Wolfram syndrome 1 gene negatively regulates ER stress signaling in rodent and human cells. J Clin Investig. 2010;120:744–55.
Lu S, Kanekura K, Hara T, Mahadevan J, Spears LD, Oslowski CM, et al. A calcium-dependent protease as a potential therapeutic target for Wolfram syndrome. Proc Natl Acad Sci USA. 2014;111:E5292–301.
Luuk H, Koks S, Plaas M, Hannibal J, Rehfeld JF, Vasar E. Distribution of Wfs1 protein in the central nervous system of the mouse and its relation to clinical symptoms of the Wolfram syndrome. J Comp Neurol. 2008;509:642–60.
Wang Z, York NW, Nichols CG, Remedi MS. Pancreatic beta cell dedifferentiation in diabetes and redifferentiation following insulin therapy. Cell Metab. 2014;19:872–82.
Hohmeier HE, Mulder H, Chen G, Henkel-Rieger R, Prentki M, Newgard CB. Isolation of INS-1-derived cell lines with robust ATP-sensitive K+ channel-dependent and -independent glucose-stimulated insulin secretion. Diabetes. 2000;49:424–30.
Clark AL, Kanekura K, Lavagnino Z, Spears LD, Abreu D, Mahadevan J, et al. Targeting cellular calcium homeostasis to prevent cytokine-mediated beta cell death. Sci Rep. 2017;7:5611.
Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29:15–21.
Liao Y, Smyth GK, Shi W. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2014;30:923–30.
Patro R, Duggal G, Love MI, Irizarry RA, Kingsford C. Salmon provides fast and bias-aware quantification of transcript expression. Nat Methods. 2017;14:417–9.
Wang L, Wang S, Li W. RSeQC: quality control of RNA-seq experiments. Bioinformatics. 2012;28:2184–5.
Robinson MD, McCarthy DJ, Smyth GK. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2010;26:139–40.
Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43:e47.
Liu R, Holik AZ, Su S, Jansz N, Chen K, Leong HS, et al. Why weight? Modelling sample and observational level variability improves power in RNA-seq analyses. Nucleic Acids Res. 2015;43:e97.
Luo W, Friedman MS, Shedden K, Hankenson KD, Woolf PJ. GAGE: generally applicable gene set enrichment for pathway analysis. BMC Bioinform. 2009;10:161.
Ishihara H, Takeda S, Tamura A, Takahashi R, Yamaguchi S, Takei D, et al. Disruption of the WFS1 gene in mice causes progressive beta-cell loss and impaired stimulus-secretion coupling in insulin secretion. Hum Mol Genet. 2004;13:1159–70.
Riggs AC, Bernal-Mizrachi E, Ohsugi M, Wasson J, Fatrai S, Welling C, et al. Mice conditionally lacking the Wolfram gene in pancreatic islet beta cells exhibit diabetes as a result of enhanced endoplasmic reticulum stress and apoptosis. Diabetologia. 2005;48:2313–21.
Yamada T, Ishihara H, Tamura A, Takahashi R, Yamaguchi S, Takei D, et al. WFS1-deficiency increases endoplasmic reticulum stress, impairs cell cycle progression and triggers the apoptotic pathway specifically in pancreatic beta-cells. Hum Mol Genet. 2006;15:1600–9.
Du K, Herzig S, Kulkarni RN, Montminy M. TRB3: a tribbles homolog that inhibits Akt/PKB activation by insulin in liver. Science. 2003;300:1574–7.
Takei D, Ishihara H, Yamaguchi S, Yamada T, Tamura A, Katagiri H, et al. WFS1 protein modulates the free Ca(2+) concentration in the endoplasmic reticulum. FEBS Lett. 2006;580:5635–40.
Hara T, Mahadevan J, Kanekura K, Hara M, Lu S, Urano F. Calcium efflux from the endoplasmic reticulum leads to beta-cell death. Endocrinology. 2014;155:758–68.
Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes. 2003;52:102–10.
Evans-Molina C, Hatanaka M, Mirmira RG. Lost in translation: endoplasmic reticulum stress and the decline of beta-cell health in diabetes mellitus. Diabetes Obes Metab. 2013;15:159–69.
Henquin JC, Ibrahim MM, Rahier J. Insulin, glucagon and somatostatin stores in the pancreas of subjects with type-2 diabetes and their lean and obese non-diabetic controls. Sci Rep. 2017;7:11015.
Noormets K, Koks S, Muldmaa M, Mauring L, Vasar E, Tillmann V. Sex differences in the development of diabetes in mice with deleted wolframin (Wfs1) gene. Exp Clin Endocrinol Diabetes. 2011;119:271–5.
Ivask M, Hugill A, Koks S. RNA-sequencing of WFS1-deficient pancreatic islets. Physiol Rep. 2016;4:e12750.
de Heredia ML, Cleries R, Nunes V. Genotypic classification of patients with Wolfram syndrome: insights into the natural history of the disease and correlation with phenotype. Genet Med. 2013;15:497–506.
Chaussenot A, Bannwarth S, Rouzier C, Vialettes B, Mkadem SA, Chabrol B, et al. Neurologic features and genotype-phenotype correlation in Wolfram syndrome. Ann Neurol. 2011;69:501–8.
Cryns K, Sivakumaran TA, Van den Ouweland JM, Pennings RJ, Cremers CW, Flothmann K, et al. Mutational spectrum of the WFS1 gene in Wolfram syndrome, nonsyndromic hearing impairment, diabetes mellitus, and psychiatric disease. Hum Mutat. 2003;22:275–87.
Scheuner D, Kaufman RJ. The unfolded protein response: a pathway that links insulin demand with beta-cell failure and diabetes. Endocr Rev. 2008;29:317–33.
Fonseca SG, Gromada J, Urano F. Endoplasmic reticulum stress and pancreatic beta-cell death. Trends Endocrinol Metab. 2011;22:266–74.
Lipson KL, Fonseca SG, Ishigaki S, Nguyen LX, Foss E, Bortell R, et al. Regulation of insulin biosynthesis in pancreatic beta cells by an endoplasmic reticulum-resident protein kinase IRE1. Cell Metab. 2006;4:245–54.
Seo HY, Kim YD, Lee KM, Min AK, Kim MK, Kim HS, et al. Endoplasmic reticulum stress-induced activation of activating transcription factor 6 decreases insulin gene expression via up-regulation of orphan nuclear receptor small heterodimer partner. Endocrinology. 2008;149:3832–41.
Cissell MA, Zhao L, Sussel L, Henderson E, Stein R. Transcription factor occupancy of the insulin gene in vivo. Evidence for direct regulation by Nkx2.2. J Biol Chem. 2003;278:751–6.
Gutierrez GD, Bender AS, Cirulli V, Mastracci TL, Kelly SM, Tsirigos A, et al. Pancreatic beta cell identity requires continual repression of non-beta cell programs. J Clin Investig. 2017;127:244–59.
Le Lay J, Stein R. Involvement of PDX-1 in activation of human insulin gene transcription. J Endocrinol. 2006;188:287–94.
Schaffer AE, Taylor BL, Benthuysen JR, Liu J, Thorel F, Yuan W, et al. Nkx6.1 controls a gene regulatory network required for establishing and maintaining pancreatic Beta cell identity. PLoS Genet. 2013;9:e1003274.
Shang L, Hua H, Foo K, Martinez H, Watanabe K, Zimmer M, et al. beta-cell dysfunction due to increased ER stress in a stem cell model of Wolfram syndrome. Diabetes. 2014;63:923–33.
Song B, Scheuner D, Ron D, Pennathur S, Kaufman RJ. Chop deletion reduces oxidative stress, improves beta cell function, and promotes cell survival in multiple mouse models of diabetes. J Clin Investig. 2008;118:3378–89.
Szabat M, Page MM, Panzhinskiy E, Skovso S, Mojibian M, Fernandez-Tajes J, et al. Reduced insulin production relieves endoplasmic reticulum stress and induces beta cell proliferation. Cell Metab. 2016;23:179–93.
Sharma RB, O’Donnell AC, Stamateris RE, Ha B, McCloskey KM, Reynolds PR, et al. Insulin demand regulates beta cell number via the unfolded protein response. J Clin Investig. 2015;125:3831–46.
Porat S, Weinberg-Corem N, Tornovsky-Babaey S, Schyr-Ben-Haroush R, Hija A, Stolovich-Rain M, et al. Control of pancreatic beta cell regeneration by glucose metabolism. Cell Metab. 2011;13:440–9.
Marchetti P, Bugliani M, Lupi R, Marselli L, Masini M, Boggi U, et al. The endoplasmic reticulum in pancreatic beta cells of type 2 diabetes patients. Diabetologia. 2007;50:2486–94.
Laybutt DR, Preston AM, Akerfeldt MC, Kench JG, Busch AK, Biankin AV, et al. Endoplasmic reticulum stress contributes to beta cell apoptosis in type 2 diabetes. Diabetologia. 2007;50:752–63.
Eizirik DL, Cnop M. ER stress in pancreatic beta cells: the thin red line between adaptation and failure. Sci Signal. 2010;3:pe7.
Urano F. Wolfram syndrome iPS cells: the first human cell model of endoplasmic reticulum disease. Diabetes. 2014;63:844–6.
Papa FR. Endoplasmic reticulum stress, pancreatic beta-cell degeneration, and diabetes. Cold Spring Harb Perspect Med. 2012;2:a007666.
Stitzel ML, Sethupathy P, Pearson DS, Chines PS, Song L, Erdos MR, et al. Global epigenomic analysis of primary human pancreatic islets provides insights into type 2 diabetes susceptibility loci. Cell Metab. 2010;12:443–55.
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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Abreu, D., Asada, R., Revilla, J.M.P. et al. Wolfram syndrome 1 gene regulates pathways maintaining beta-cell health and survival. Lab Invest 100, 849–862 (2020). https://doi.org/10.1038/s41374-020-0408-5
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