title: Asna1/TRC40 Controls β-Cell Function and Endoplasmic Reticulum Homeostasis by Ensuring Retrograde Transport.
abstract: Type 2 diabetes (T2D) is characterized by insulin resistance and β-cell failure. Insulin resistance per se, however, does not provoke overt diabetes as long as compensatory β-cell function is maintained. The increased demand for insulin stresses the β-cell endoplasmic reticulum (ER) and secretory pathway, and ER stress is associated with β-cell failure in T2D. The tail recognition complex (TRC) pathway, including Asna1/TRC40, is implicated in the maintenance of endomembrane trafficking and ER homeostasis. To gain insight into the role of Asna1/TRC40 in maintaining endomembrane homeostasis and β-cell function, we inactivated Asna1 in β-cells of mice. We show that Asna1(β-/-) mice develop hypoinsulinemia, impaired insulin secretion, and glucose intolerance that rapidly progresses to overt diabetes. Loss of Asna1 function leads to perturbed plasma membrane-to-trans Golgi network and Golgi-to-ER retrograde transport as well as to ER stress in β-cells. Of note, pharmacological inhibition of retrograde transport in isolated islets and insulinoma cells mimicked the phenotype of Asna1(β-/-) β-cells and resulted in reduced insulin content and ER stress. These data support a model where Asna1 ensures retrograde transport and, hence, ER and insulin homeostasis in β-cells.
authors.affiliation: Umeå Centre for Molecular Medicine, Umeå University, Umeå, Sweden.
authors.forename: Stefan
authors.initials: S
authors.lastname: Norlin
authors.affiliation: Umeå Centre for Molecular Medicine, Umeå University, Umeå, Sweden.
authors.forename: Vishal S
authors.initials: VS
authors.lastname: Parekh
authors.affiliation: Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg.
authors.forename: Peter
authors.initials: P
authors.lastname: Naredi
authors.affiliation: Umeå Centre for Molecular Medicine, Umeå University, Umeå, Sweden helena.edlund@umu.se.
authors.forename: Helena
authors.initials: H
authors.lastname: Edlund
mesh_terms: D000818:Animals; D053501:Arsenite Transporting ATPases / Q000235:genetics* / Q000378:metabolism; D001549:Benzamides / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism*; D018149:Glucose Intolerance / Q000235:genetics / Q000378:metabolism; D006056:Golgi Apparatus / Q000187:drug effects / Q000378:metabolism; D006706:Homeostasis / Q000235:genetics; D066298:In Vitro Techniques; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D050765:Qa-SNARE Proteins / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D013876:Thiophenes / Q000494:pharmacology
chemical_list: C549073:2-(((5-methyl-2-thienyl)methylene)amino)-N-phenylbenzamide; D001549:Benzamides; D001786:Blood Glucose; D007328:Insulin; D050765:Qa-SNARE Proteins; D013876:Thiophenes; D053501:Arsenite Transporting ATPases; C506972:Asna1 protein, mouse