Human Molecular Genetics Advance Access published online on October 18, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm296
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Sodium-potassium ATPase beta 1 subunit is a molecular partner of Wolframin, an endoplasmic reticulum (ER) protein involved in ER stress
1 Section of Medical and Molecular Genetics, The Medical School, University of Birmingham, Birmingham B15, 2TT, UK 2 Department of Cell Biology, Division of Medicine, Sir Alexander Fleming Building, Imperial College, Exhibition Road, London SW7 2AZ, UK 3 Institute of Microbiology and Laboratory Diagnostics, Robert-Koch-Allee 2 D-82131 Gauting, Germany
* Address for correspondence: Timothy G Barrett, Diabetes Unit, Birmingham Children's Hospital, Steelhouse Lane, Birmingham B4 6 NH, UK Tel. (0)121 333 9267, Fax (0)121 333 9272. Email: t.g.barrett{at}bham.ac.uk
Received April 20, 2007; Revised September 30, 2007; Accepted September 30, 2007
Wolfram syndrome, an autosomal recessive disorder characterised by diabetes mellitus and optic atrophy, is caused by mutations in the WFS1 gene encoding an endoplasmic reticulum (ER) membrane protein, Wolframin. Although its precise functions are unknown, Wolframin deficiency increases ER stress, impairs cell cycle progression and affects calcium homeostasis. To gain further insight into its function and identify molecular partners, we used the WFS1-carboxy-terminal domain as bait in a yeast two-hybrid screen with a human brain cDNA library. Na+/K+ ATPase ß1 subunit was identified as an interacting clone. We mapped the interaction to the WFS1 carboxy-terminal and transmembrane domains, but not the amino-terminal domain. Our mapping data suggest that the interaction most likely occurs in the ER. We confirmed the interaction by co-immunoprecipitation in mammalian cells, and with endogenous proteins in JEG3 placental cells, neuroblastoma SKNAS and pancreatic MIN6 ß cells. Na+/K+ ATPase ß1 subunit expression was reduced in plasma membrane fractions of human WFS1 mutant fibroblasts and WFS1 knock down MIN6 pancreatic ß-cells compared with wild type cells; Na+/K+ ATPase 
1 subunit expression was also reduced in WFS-depleted MIN6 ß cells. Induction of ER stress in wild type cells only partly accounted for the reduced Na+/K+ ATPase ß1 subunit expression observed. We conclude that the interaction may be important for Na+/K+ ATPase ß1 subunit maturation; loss of this interaction may contribute to the pathology seen in Wolfram syndrome via reductions in sodium pump 1 and ß1 subunit expression in pancreatic ß cells.
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