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Sarco(endo)plasmic reticulum ATPase is a molecular partner of Wolfram syndrome 1 protein, which negatively regulates its expression.
Zatyka, Malgorzatta Xavier, Gabriela Da Silva Bellomo, Elisa A. Leadbeater, Wendy Astuti, Dewi Smith, Joel Michelangeli, Francesco Rutter, Guy A. Barrett, Timothy G.
Zatyka, Malgorzatta
Xavier, Gabriela Da Silva
Bellomo, Elisa A.
Leadbeater, Wendy
Astuti, Dewi
Smith, Joel
Michelangeli, Francesco
Rutter, Guy A.
Barrett, Timothy G.
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2015-02-01
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Abstract
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 Ca(2+) 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 Ca(2+) concentration ([Ca(2+)]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.
Citation
Zatyka, M., Xavier, G. D. S., Bellomo, E. A., Leadbeater, W., Astuti, D., Smith, J., Michelangeli, F., Rutter, G. A., Barrett, T. G. (2015). Sarco(endo)plasmic reticulum ATPase is a molecular partner of Wolfram syndrome 1 protein, which negatively regulates its expression. Human Molecular Genetics, 24(3), 814-27. http://dx.doi.org/10.1093/hmg/ddu499
Publisher
Oxford University Press
Journal
Human Molecular Genetics
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Article
Language
en
Description
This is a pre-copyedited, author-produced PDF of an article accepted for publication in Human Molecular Genetics following peer review. The version of record Zatyka, M., Xavier, G. D. S., Bellomo, E. A., Leadbeater, W., Astuti, D., Smith, J., Michelangeli, F., Rutter, G. A., Barrett, T. G. (2015). Sarco(endo)plasmic reticulum ATPase is a molecular partner of Wolfram syndrome 1 protein, which negatively regulates its expression. Human Molecular Genetics, 24(3), 814-27 is available online at: http://dx.doi.org/10.1093/hmg/ddu499
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ISSN
0964-6906
EISSN
1460-2083