title: Wolfram syndrome 1 and adenylyl cyclase 8 interact at the plasma membrane to regulate insulin production and secretion.
abstract: Endoplasmic reticulum (ER) stress causes pancreatic β-cell dysfunction and contributes to β-cell loss and the progression of type 2 diabetes. Wolfram syndrome 1 (WFS1) has been shown to be an important regulator of the ER stress signalling pathway; however, its role in β-cell function remains unclear. Here we provide evidence that WFS1 is essential for glucose- and glucagon-like peptide 1 (GLP-1)-stimulated cyclic AMP production and regulation of insulin biosynthesis and secretion. Stimulation with glucose causes WFS1 translocation from the ER to the plasma membrane, where it forms a complex with adenylyl cyclase 8 (AC8), an essential cAMP-generating enzyme in the β-cell that integrates glucose and GLP-1 signalling. ER stress and mutant WFS1 inhibit complex formation and activation of AC8, reducing cAMP synthesis and insulin secretion. These findings reveal that an ER-stress-related protein has a distinct role outside the ER regulating both insulin biosynthesis and secretion. The reduction of WFS1 protein on the plasma membrane during ER stress is a contributing factor for β-cell dysfunction and progression of type 2 diabetes.
authors.affiliation: Cardiovascular and Metabolism Disease Area, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA. sonya.fonseca@novartis.com
authors.forename: Sonya G
authors.initials: SG
authors.lastname: Fonseca
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Urano
authors.forename: Gordon C
authors.initials: GC
authors.lastname: Weir
authors.forename: Jesper
authors.initials: J
authors.lastname: Gromada
authors.forename: Mark
authors.initials: M
authors.lastname: Burcin
mesh_terms: D000262:Adenylyl Cyclases / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000096:biosynthesis; D059865:Endoplasmic Reticulum Stress; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000096:biosynthesis* / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
chemical_list: D007328:Insulin; D008565:Membrane Proteins; C114987:wolframin protein; D052216:Glucagon-Like Peptide 1; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; C118292:adenylyl cyclase 8; D005947:Glucose