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A targeted RNAi screen identifies endocytic trafficking factors that control GLP-1 receptor signaling in pancreatic beta cells

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Title: A targeted RNAi screen identifies endocytic trafficking factors that control GLP-1 receptor signaling in pancreatic beta cells
Authors: Buenaventura, T
Kanda, N
Douzenis, PC
Jones, B
Bloom, SR
Chabosseau, P
Corrêa, IR
Bosco, D
Piemonti, L
Marchetti, P
Johnson, PR
Shapiro, AJ
Rutter, GA
Tomas, A
Item Type: Journal Article
Abstract: The GLP-1 receptor (GLP-1R) is a key target for type 2 diabetes (T2D) treatment. Since endocytic trafficking of agonist-bound receptors is one of the most important routes for regulation of receptor signaling, a better understanding of this process may facilitate the development of new T2D therapeutic strategies. Here, we have screened 29 proteins with known functions in G protein-coupled receptor trafficking for their role in GLP-1R potentiation of insulin secretion in pancreatic beta cells. We identify five (clathrin, dynamin1, AP2, SNX27 and SNX1) that increase and four (HIP1, HIP14, GASP-1 and Nedd4) that decrease insulin secretion from murine insulinoma MIN6B1 cells in response to the GLP-1 analogue exendin-4. The roles of Huntingtin-interacting protein 1 (HIP1) and the endosomal sorting nexins SNX1 and SNX27 were further characterized in mouse and human beta cell lines and human islets. While HIP1 was required for the coupling of cell surface GLP-1R activation with clathrin-dependent endocytosis, the sorting nexins were found to control the balance between GLP-1R plasma membrane recycling and lysosomal degradation, and, in doing so, determine the overall beta cell incretin responses. We thus identify key modulators of GLP-1R trafficking and signaling that might provide novel targets to enhance insulin secretion in T2D.
Issue Date: 28-Dec-2017
Date of Acceptance: 19-Dec-2017
URI: http://hdl.handle.net/10044/1/55694
DOI: 10.2337/db17-0639
ISSN: 0012-1797
Publisher: American Diabetes Association
Start Page: 385
End Page: 399
Journal / Book Title: Diabetes
Volume: 67
Issue: 3
Copyright Statement: © 2017 by the American Diabetes Association. http://www.diabetesjournals.org/content/license Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.
Sponsor/Funder: Medical Research Council
Funder's Grant Number: MR/M012646/1
Keywords: 11 Medical And Health Sciences
Endocrinology & Metabolism
Publication Status: Published
Appears in Collections:Department of Medicine
Faculty of Medicine



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