WFS1

Wolframin (WFS1) is a multi-pass transmembrane glycoprotein primarily localized to the endoplasmic reticulum (ER) membrane and mitochondria-associated ER membranes (MAMs). The protein plays essential roles in ER calcium homeostasis by positively modulating ER Ca2+ levels through increasing the rate of Ca2+ uptake [PMID:16989814]. WFS1 also functions as a negative regulator of ER stress signaling, particularly by suppressing ATF6alpha-mediated unfolded protein response through stabilization of the E3 ubiquitin ligase HRD1 and promotion of ATF6alpha proteasomal degradation [PMID:20160352]. Additionally, WFS1 interacts with and stabilizes V-ATPase subunit ATP6V1A and Na+/K+-ATPase beta1 subunit (ATP1B1), regulating their expression and stability [PMID:23035048, PMID:17947299]. Mutations in WFS1 cause Wolfram syndrome (DIDMOAD - diabetes insipidus, diabetes mellitus, optic atrophy, deafness), characterized by progressive beta-cell loss and neurodegeneration due to dysregulated ER stress and calcium homeostasis.

Disorders

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