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

Abstract

Wolfram syndrome is an autosomal-recessive disorder characterized by insulin-dependent diabetes mellitus, caused by nonautoimmune loss of β 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 6α (ATF6α), through the ubiquitin-proteasome pathway. WFS1 suppressed expression of ATF6α target genes and repressed ATF6α-mediated activation of the ER stress response element (ERSE) promoter. Moreover, WFS1 stabilized the E3 ubiquitin ligase HRD1, brought ATF6α to the proteasome, and enhanced its ubiquitination and proteasome-mediated degradation, leading to suppression of ER stress signaling. Consistent with these data, β cells from WFS1-deficient mice and lymphocytes from patients with Wolfram syndrome exhibited dysregulated ER stress signaling through upregulation of ATF6α 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 β cell death in diabetes.

A calcium-dependent protease as a potential therapeutic target for Wolfram syndrome

“…It has been shown that WFS1-deficient pancreatic β cells have high baseline ER stress levels and impaired insulin synthesis and secretion. Thus, WFS1-deficient β cells are susceptible to ER stress mediated cell death (5,6,32,(40)(41)(42). The functions of WFS2 are still not clear.…”

“…It follows that genetic or acquired ER dysfunction can trigger a variety of common diseases, including neurodegenerative diseases, metabolic disorders, and inflammatory bowel disease (3,4). Breakdown in ER function is also associated with genetic disorders such as Wolfram syndrome (5)(6)(7)(8). It is challenging to determine the exact effects of ER dysfunction on the fate of affected cells in common diseases with polygenic and multifactorial etiologies.…”

Modelling the effect of GRP78 on anti-oestrogen sensitivity and resistance in breast cancer

“…other chaperones) release the sensors for further activation upon additional EnR stress (reviewed in Ma & Hendershot [30]). While numerous chaperones are likely to play a role in sensor inhibition, such as BI-1 [31,32], AIP1 [33] and RACK1 [34] for IRE1, and WFS1 [35] for ATF6, for simplicity of the model, we lump the effects of these other chaperones into the effect of a single chaperone, GRP94. While not redundant to GRP78, GRP94 plays an important role in EnR stress control [36][37][38].…”

Genotypic classification of patients with Wolfram syndrome: insights into the natural history of the disease and correlation with phenotype

“…22 Mutations in WFS1 are deleterious for protein expression. 23,24 WFS1 depletion in cells induces high levels of endoplasmic reticulum stress, activating the unfolded protein response, 25,26 and affects insulin processing and secretion. 27,28 Glycosylation sites were identified as important for protein stability, 22 and a region that targets unfolded WFS1 to degradation (degron) has been identified.…”