WFS1-deficiency increases endoplasmic reticulum stress, impairs cell cycle progression and triggers the apoptotic pathway specifically in pancreatic β-cells

Abstract

Wolfram syndrome, an autosomal recessive disorder associated with diabetes mellitus and optic atrophy, is caused by mutations in the WFS1 gene encoding an endoplasmic reticulum (ER) membrane protein. Herein, we report that pancreatic islets of wfs1-deficient mice exhibit increases in phosphorylation of RNA-dependent protein kinase-like ER kinase, chaperone gene expressions and active XBP1 protein levels, indicating an enhanced ER stress response. We established wfs1-deficient MIN6 clonal beta-cells by crossing wfs1-deficient mice with mice expressing simian virus 40 large T antigen in beta-cells. These cells show essentially the same alterations in ER stress responses as wfs1-deficient islets, which were reversed by re-expression of WFS1 protein or overexpression of GRP78, a master regulator of the ER stress response. In contrast, these changes are not observed in heart, skeletal muscle or brown adipose tissues with WFS1-deficiency. The increased ER stress response was accompanied by reduced BrdU incorporation and increased caspase-3 cleavage, indicating impaired cell cycle progression and accelerated apoptotic processes in the mutant islets. These changes are associated with increased expression of the cell cycle regulator p21(CIP1) in wfs1-deficient islets and clonal beta-cells. Treatment of islets with thapsigargin, an ER stress inducer, caused upregulation of p21(CIP1). In addition, forced expression of p21(CIP1) resulted in reduced MIN6 beta-cell numbers, suggesting the ER stress-induced increase in p21(CIP1) expression to be involved in beta-cell loss in the mutant islets. These data indicate that WFS1-deficiency activates the ER stress response specifically in beta-cells, causing beta-cell loss through impaired cell cycle progression and increased apoptosis.

Increased insulin demand promotes while pioglitazone prevents pancreatic beta cell apoptosis in Wfs1 knockout mice

“…ER stress induces WFS1 protein production and lack of this protein itself enhances the UPR [15,[19][20][21]. This was true in our mice (Fig.…”

“…unexpectedly with the C57BL/6J background, there is no apparent increase in blood glucose levels even at 36 weeks [15]. Because beta cells of Wfs1 −/− mice were also shown to be susceptible to ER stress in ex-vivo experiments and cultured cells [15,21], we sought to test this in the in vivo model. Fig.…”

“…However, it is certain that its function is closely related to ER stress responses. ER stress induces Wfs1 expression and, in turn, loss of WFS1 protein exacerbates ER stress [15,[19][20][21]. Furthermore, Wfs1 −/− islet cells are susceptible to ER stress-induced apoptosis [15,21,22].…”

“…ER stress induces Wfs1 expression and, in turn, loss of WFS1 protein exacerbates ER stress [15,[19][20][21]. Furthermore, Wfs1 −/− islet cells are susceptible to ER stress-induced apoptosis [15,21,22]. ER stress is induced under conditions such as overload of protein synthesis/processing, accumulation of structurally abnormal proteins, disturbance of post-translational modification and ER calcium homeostasis abnormalities.…”

Impact of polymorphisms in WFS1 on prediabetic phenotypes in a population-based sample of middle-aged people with normal and abnormal glucose regulation

“…Disruption of Wfs1 in mice resulted in progressive glucose intolerance and concomitant insulin deficiency. In this animal model, beta cell death occurred by an accelerated process of apoptosis; similarly, increased levels of markers reflecting ER stress were also demonstrated [7][8][9]. In line with the outcome of studies in mice, previous and statistically undersized human studies have indicated that variation in WFS1 may be associated with type 1 diabetes mellitus [10], type 2 diabetes mellitus [11] and a combination of diabetes mellitus and deafness [12,13].…”