RRC ID 34822
Author Norlin S, Parekh VS, Naredi P, Edlund H.
Title Asna1/TRC40 Controls β-Cell Function and Endoplasmic Reticulum Homeostasis by Ensuring Retrograde Transport.
Journal Diabetes
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.
Volume 65(1)
Pages 110-9
Published 2016-1-1
DOI 10.2337/db15-0699
PII db15-0699
PMID 26438609
MeSH Animals Arsenite Transporting ATPases / genetics* Arsenite Transporting ATPases / metabolism Benzamides / pharmacology Blood Glucose / metabolism* Blotting, Western Cell Line, Tumor Cell Membrane / drug effects Cell Membrane / metabolism Diabetes Mellitus, Type 2 / genetics* Diabetes Mellitus, Type 2 / metabolism Endoplasmic Reticulum / drug effects Endoplasmic Reticulum / metabolism* Endoplasmic Reticulum Stress Endosomes / drug effects Endosomes / metabolism* Glucose Intolerance / genetics Glucose Intolerance / metabolism Golgi Apparatus / drug effects Golgi Apparatus / metabolism Homeostasis / genetics In Vitro Techniques Insulin / blood Insulin / metabolism* Insulin Secretion Insulin-Secreting Cells / metabolism* Intracellular Membranes / drug effects Intracellular Membranes / metabolism* Islets of Langerhans / metabolism Mice Mice, Knockout Qa-SNARE Proteins / metabolism Real-Time Polymerase Chain Reaction Thiophenes / pharmacology
IF 7.72
Times Cited 12
Mice RBRC01099