title: Endoplasmic reticulum stress and N-glycosylation modulate expression of WFS1 protein.
abstract: Mutations of the WFS1 gene are responsible for two hereditary diseases, Wolfram syndrome and low frequency sensorineural hearing loss. The WFS1 protein is a glycoprotein located in the endoplasmic reticulum (ER) membrane but its function is poorly understood. Herein we show WFS1 mRNA and protein levels in pancreatic islets to be increased with ER-stress inducers, thapsigargin and dithiothreitol. Another ER-stress inducer, the N-glycosylation inhibitor tunicamycin, also raised WFS1 mRNA but not protein levels. Site-directed mutagenesis showed both Asn-663 and Asn-748 to be N-glycosylated in mouse WFS1 protein. The glycosylation-defective WFS1 protein, in which Asn-663 and Asn-748 had been substituted with aspartate, exhibited an increased protein turnover rate. Consistent with this, the WFS1 protein was more rapidly degraded in the presence of tunicamycin. These data indicate that ER-stress and N-glycosylation play important roles in WFS1 expression and stability, and also suggest regulatory roles for this protein in ER-stress induced cell death.
authors.affiliation: Division of Molecular Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan.
authors.forename: Suguru
authors.initials: S
authors.lastname: Yamaguchi
authors.forename: Hisamitsu
authors.initials: H
authors.lastname: Ishihara
authors.forename: Akira
authors.initials: A
authors.lastname: Tamura
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yamada
authors.forename: Rui
authors.initials: R
authors.lastname: Takahashi
authors.forename: Daisuke
authors.initials: D
authors.lastname: Takei
authors.forename: Hideki
authors.initials: H
authors.lastname: Katagiri
authors.forename: Yoshitomo
authors.initials: Y
authors.lastname: Oka
mesh_terms: D000818:Animals; D004229:Dithiothreitol / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D006031:Glycosylation; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016297:Mutagenesis, Site-Directed; D019284:Thapsigargin / Q000494:pharmacology; D014415:Tunicamycin / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D008565:Membrane Proteins; C114987:wolframin protein; D014415:Tunicamycin; D019284:Thapsigargin; D004229:Dithiothreitol