Journal
HUMAN MOLECULAR GENETICS
Volume 24, Issue 3, Pages 814-827Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddu499
Keywords
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Funding
- Wellcome Trust [067081/Z/02/Z, 081958/Z/07/Z]
- Medical Research Council [90401641]
- European Union (FP6 'Save-beta')
- Imperial College Divisional Studentship
- Birmingham Children's Hospital Research Foundation
- Thames Honda
- Wellchild
- Wellcome Trust VIP award
- European Commission [2010 12 05]
- MRC [MR/K001981/1] Funding Source: UKRI
- Medical Research Council [MR/K001981/1] Funding Source: researchfish
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Wolfram syndrome is an autosomal recessive disorder characterized by neurodegeneration and diabetes mellitus. The gene responsible for the syndrome (WFS1) encodes an endoplasmic reticulum (ER)-resident transmembrane protein that is involved in the regulation of the unfolded protein response (UPR), intracellular ion homeostasis, cyclic adenosine monophosphate production and regulation of insulin biosynthesis and secretion. In this study, single cell Ca2+ imaging with fura-2 and direct measurements of free cytosolic ATP concentration ([ATP](CYT)) with adenovirally expressed luciferase confirmed a reduced and delayed rise in cytosolic free Ca2+ concentration ([Ca2+](CYT)), and additionally, diminished [ATP](CYT) rises in response to elevated glucose concentrations in WFS1-depleted MIN6 cells. We also observed that sarco(endo)plasmic reticulum ATPase (SERCA) expression was elevated in several WFS1-depleted cell models and primary islets. We demonstrated a novel interaction between WFS1 and SERCA by co-immunoprecipitation in Cos7 cells and with endogenous proteins in human neuroblastoma cells. This interaction was reduced when cells were treated with the ER stress inducer dithiothreitol. Treatment of WFS1-depleted neuroblastoma cells with the proteasome inhibitor MG132 resulted in reduced accumulation of SERCA levels compared with wild-type cells. Together these results reveal a role for WFS1 in the negative regulation of SERCA and provide further insights into the function of WFS1 in calcium homeostasis.
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