WFS1 functions in ER export of vesicular cargo proteins in pancreatic β-cells

Abstract

The sorting of soluble secretory proteins from the endoplasmic reticulum (ER) to the Golgi complex is mediated by coat protein complex II (COPII) vesicles and thought to required specific ER membrane cargo-receptor proteins. However, these receptors remain largely unknown. Herein, we show that ER to Golgi transfer of vesicular cargo proteins requires WFS1, an ER-associated membrane protein whose loss of function leads to Wolfram syndrome. Mechanistically, WFS1 directly binds to vesicular cargo proteins including proinsulin via its ER luminal C-terminal segment, whereas pathogenic mutations within this region disrupt the interaction. The specific ER export signal encoded in the cytosolic N-terminal segment of WFS1 is recognized by the COPII subunit SEC24, generating mature COPII vesicles that traffic to the Golgi complex. WFS1 deficiency leads to abnormal accumulation of proinsulin in the ER, impeding the proinsulin processing as well as insulin secretion. This work identifies a vesicular cargo receptor for ER export and suggests that impaired peptide hormone transport underlies diabetes resulting from pathogenic WFS1 mutations.

Integrated multimodality microscope for accurate and efficient target-guided cryo-lamellae preparation

“…Mitochondria were stained with 1 μM MitoTracker Deep Red (M22426, Thermo Fisher Scientific) at 37 °C for 30 min. For the validation of the MERC, the cells were transiently transfected with ER-DsRed for endoplasmic reticulum labeling 54 .…”

MCT1-dependent energetic failure and neuroinflammation underlie optic nerve degeneration in Wolfram syndrome mice

“…As a consequence, Wolframin loss results in the Ca 2+ leakage from the ER with a simultaneous increase of its cytosolic concentration, activation of the Ca 2+ -dependent protease calpain which, in turn, activates programmed apoptosis (Lu et al, 2014;Takei et al, 2006). Moreover, recent findings have suggested that Wolframin is required for the proper release of both insulin and neurotransmitters from the ER and their delivery to the cell periphery through assisted vesicle trafficking (Wang et al, 2021). Increasing reports have described dysfunctional ER-mitochondria communication caused by Wolframin loss.…”

Wolfram syndrome 1b mutation suppresses Mauthner-cell axon regeneration via ER stress signal pathway

“…WS patients had the clinical symptoms of visual field defects, cerebellar ataxia, epilepsy, anxiety, and cognitive impairment from neurological aspects [ 4 , 5 ]. Subsequently, neuroimaging results showed that WS patients developed generalized brain atrophy, particularly in the cerebellum, medulla, and pons [ 6 – 11 ]. However, there is no effective treatment for WS.…”

“…The WFS1 protein, encoded by the wfs1 gene, is an integral membrane protein located in the endoplasmic reticulum (ER), and the mutation of the wfs1 gene is identified as the leading causative factor of WS. The functions of WFS1 have been extensively investigated in beta cells due to their abundance in the pancreas [ 6 , 12 – 14 ]. This protein is also plentiful in the brain, particularly in the hippocampus, hypothalamus, cerebellum, and brainstem, indicating the prominent importance of WFS1 in the central nervous system (CNS) [ 15 , 16 ].…”

“…The mRNA expression level of wfs1 was upregulated in response to ER stress [ 26 ]. Concurrently, the ER stress response was stimulated by the WFS1 deficiency, which led to dysfunction of the pancreatic islets and the nervous system in the wfs1 -deficient rats and WS patients, indicating that WFS1 is related to the ER stress response [ 6 , 11 – 14 , 17 , 27 ].…”