Sonya G. Fonseca

WFS1 is a novel component of the unfolded protein response and maintains homeostasis of the endoplasmic reticulum in pancreatic beta-cells

In Wolfram syndrome, a rare form of juvenile diabetes, pancreatic β-cell death is not accompanied by an autoimmune response. Although it has been reported that mutations in the WFS1 gene are responsible for the development of this syndrome, the precise molecular mechanisms underlying β-cell death caused by the WFS1 mutations remain unknown. Here we report that WFS1 is a novel component of the unfolded protein response and has an important function in maintaining homeostasis of the endoplasmic reticulum (ER) in pancreatic β-cells. WFS1 encodes a transmembrane glyco-protein in the ER. WFS1 mRNA and protein are induced by ER stress. The expression of WFS1 is regulated by inositol requiring 1 and PKR-like ER kinase, central regulators of the unfolded protein response. WFS1 is normally up-regulated during insulin secretion, whereas inactivation of WFS1 in β-cells causes ER stress and β-cell dysfunction. These results indicate that the pathogenesis of Wolfram syndrome involves chronic ER stress in pancreatic β-cells caused by the loss of function of WFS1.

Wolfram syndrome 1 gene negatively regulates ER stress signaling in rodent and human cells

Wolfram syndrome is an autosomal-recessive disorder characterized by insulin-dependent diabetes mellitus, caused by nonautoimmune loss of beta cells, and neurological dysfunctions. We have previously shown that mutations in the Wolfram syndrome 1 (WFS1) gene cause Wolfram syndrome and that WFS1 has a protective function against ER stress. However, it remained to be determined how WFS1 mitigates ER stress. Here we have shown in rodent and human cell lines that WFS1 negatively regulates a key transcription factor involved in ER stress signaling, activating transcription factor 6alpha (ATF6alpha), through the ubiquitin-proteasome pathway. WFS1 suppressed expression of ATF6alpha target genes and repressed ATF6alpha-mediated activation of the ER stress response element (ERSE) promoter. Moreover, WFS1 stabilized the E3 ubiquitin ligase HRD1, brought ATF6alpha to the proteasome, and enhanced its ubiquitination and proteasome-mediated degradation, leading to suppression of ER stress signaling. Consistent with these data, beta cells from WFS1-deficient mice and lymphocytes from patients with Wolfram syndrome exhibited dysregulated ER stress signaling through upregulation of ATF6alpha and downregulation of HRD1. These results reveal a role for WFS1 in the negative regulation of ER stress signaling and in the pathogenesis of diseases involving chronic, unresolvable ER stress, such as pancreatic beta cell death in diabetes.

Endoplasmic reticulum stress and pancreatic β-cell death

In pancreatic β-cells, the endoplasmic reticulum (ER) is an important cellular compartment for insulin biosynthesis, which accounts for half of the total protein production in these cells. Protein flux through the ER must be carefully monitored to prevent dysregulation of ER homeostasis and stress. ER stress elicits a signaling cascade known as the unfolded protein response (UPR), which influences both life and death decisions in cells. β-cell loss is a pathological component of both type 1 and type 2 diabetes, and recent findings suggest that ER stress is involved. In this review, we address the transition from the physiological ER stress response to the pathological response, and explore the mechanisms of ER stress-mediated β-cell loss during the progression of diabetes.

Endoplasmic reticulum stress in beta-cells and development of diabetes

The endoplasmic reticulum (ER) is a cellular compartment responsible for multiple important cellular functions including the biosynthesis and folding of newly synthesized proteins destined for secretion, such as insulin. A myriad of pathological and physiological factors perturb ER function and cause dysregulation of ER homeostasis, leading to ER stress. ER stress elicits a signaling cascade to mitigate stress, the unfolded protein response (UPR). As long as the UPR can relieve stress, cells can produce the proper amount of proteins and maintain ER homeostasis. If the UPR, however, fails to maintain ER homeostasis, cells will undergo apoptosis. Activation of the UPR is critical to the survival of insulin-producing pancreatic beta-cells with high secretory protein production. Any disruption of ER homeostasis in beta-cells can lead to cell death and contribute to the pathogenesis of diabetes. There are several models of ER-stress-mediated diabetes. In this review, we outline the underlying molecular mechanisms of ER-stress-mediated beta-cell dysfunction and death during the progression of diabetes.

Endoplasmic Reticulum Stress-Induced Apoptosis and Autoimmunity in Diabetes

Increasing evidence suggests that stress signaling pathways emanating from the endoplasmic reticulum (ER) are important to the pathogenesis of both type 1 and type 2 diabetes. Recent observations indicate that ER stress signaling participates in maintaining the ER homeostasis of pancreatic beta-cells. Either a high level of ER stress or defective ER stress signaling in beta-cells may cause an imbalance in ER homeostasis and lead to beta-cell apoptosis and autoimmune response. In addition, it has been suggested that ER stress attributes to insulin resistance in patients with type 2 diabetes. It is necessary to study the relationship between ER stress and diabetes in order to develop new therapeutic approaches to diabetes based on drugs that block the ER stress-mediated cell-death pathway and insulin resistance.

Wolfram syndrome 1 and adenylyl cyclase 8 interact at the plasma membrane to regulate insulin production and secretion.

Endoplasmic reticulum (ER) stress causes pancreatic β-cell dysfunction and contributes to β-cell loss and the progression of type 2 diabetes. Wolfram syndrome 1 (WFS1) has been shown to be an important regulator of the ER stress signalling pathway; however, its role in β-cell function remains unclear. Here we provide evidence that WFS1 is essential for glucose- and glucagon-like peptide 1 (GLP-1)-stimulated cyclic AMP production and regulation of insulin biosynthesis and secretion. Stimulation with glucose causes WFS1 translocation from the ER to the plasma membrane, where it forms a complex with adenylyl cyclase 8 (AC8), an essential cAMP-generating enzyme in the β-cell that integrates glucose and GLP-1 signalling. ER stress and mutant WFS1 inhibit complex formation and activation of AC8, reducing cAMP synthesis and insulin secretion. These findings reveal that an ER-stress-related protein has a distinct role outside the ER regulating both insulin biosynthesis and secretion. The reduction of WFS1 protein on the plasma membrane during ER stress is a contributing factor for β-cell dysfunction and progression of type 2 diabetes.

Stress hypERactivation in the β-cell.

In pancreatic β-cells, the endoplasmic reticulum (ER) is the crucial site for insulin biosynthesis, as this is where the protein-folding machinery for secretory proteins is localized. Perturbations to ER function of the β-cell, such as a high demand for insulin secretion, can lead to an imbalance in protein homeostasis and lead to ER stress. This stress can be mitigated by an adaptive, cellular response, the unfolded protein response (UPR). UPR activation is vital to the survival of β-cells, as these cells represent one of the most susceptible tissues for ER stress, due to their highly secretory function. However, in some cases, this response is not sufficient to relieve stress, leading to apoptosis and contributing to the pathogenesis of diabetes. Recent evidence shows that ER stress plays a significant role in both type 1 and type 2 diabetes. In this review, we outline the mechanisms of ER stress-mediated β-cell death and focus on the role of ER stress in various forms of diabetes, particularly a genetic form of diabetes called Wolfram syndrome.

Valproate, a mood stabilizer, induces WFS1 expression and modulates its interaction with ER stress protein GRP94

Background Valproate is a standard treatment for bipolar disorder and a first-line mood stabilizer. The molecular mechanisms underlying its actions in bipolar disorder are unclear. It has been suggested that the action of valproate is linked to changes in gene expression and induction of endoplasmic reticulum (ER) stress-response proteins. Principal Findings Here we show that valproate modulates the ER stress response through the regulation of WFS1, an important component for mitigating ER stress. Therapeutic concentrations of valproate induce expression of WFS1 mRNA and activate the WFS1 promoter. In addition, WFS1 forms a complex with GRP94, an ER stress-response protein, in which valproate dose-dependently enhances its dissociation from GRP94. Conclusions These results suggest that the therapeutic effects of valproate in bipolar disorder may be mediated by WFS1 expression and its dissociation from GRP94.