A Targeted RNAi Screen Identifies Endocytic Trafficking Factors That Control GLP-1 Receptor Signaling in Pancreatic β-Cells

Article Article scientifique Article A Targeted RNAi Screen Identifies Endocytic Trafficking Factors That Control GLP-1 Receptor Signaling in Pancreatic β-Cells eng 2018 author Buenaventura Teresa author Kanda Nisha author Douzenis Phoebe C author Jones Ben author Bloom Stephen R author Chabosseau Pauline author Corrêa Ivan R (Jr) author Bosco Domenico 23285 author Piemonti Lorenzo author Marchetti Piero author Johnson Paul R author Shapiro A M James author Rutter Guy Allen 48078 author Tomas Catala Alejandra Del Don 135260 385-399 10.2337/db17-0639 29284659 0012-1797 http://diabetes.diabetesjournals.org/content/67/3/385 The glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) is a key target for type 2 diabetes (T2D) treatment. Because 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 screened 29 proteins with known functions in G protein-coupled receptor trafficking for their role in GLP-1R potentiation of insulin secretion in pancreatic β-cells. We identify five (clathrin, dynamin1, AP2, sorting nexins [SNX] SNX27, and SNX1) that increase and four (huntingtin-interacting protein 1 [HIP1], HIP14, GASP-1, and Nedd4) that decrease insulin secretion from murine insulinoma MIN6B1 cells in response to the GLP-1 analog exendin-4. The roles of HIP1 and the endosomal SNX1 and SNX27 were further characterized in mouse and human β-cell lines and human islets. While HIP1 was required for the coupling of cell surface GLP-1R activation with clathrin-dependent endocytosis, the SNXs were found to control the balance between GLP-1R plasma membrane recycling and lysosomal degradation and, in doing so, determine the overall β-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. 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. Animals Calcium Signaling/drug effects Cell Line Cyclic AMP/metabolism DNA-Binding Proteins/antagonists & inhibitors/genetics/metabolism Endocytosis/drug effects Exenatide Glucagon-Like Peptide-1 Receptor/agonists/genetics/metabolism Humans Incretins/pharmacology Insulin/metabolism Insulin Secretion Insulin-Secreting Cells/drug effects/metabolism/ultrastructure Lysosomes/drug effects/enzymology/metabolism/ultrastructure Mice Microscopy Electron Transmission Peptides/pharmacology RNA Interference Recombinant Fusion Proteins/chemistry/metabolism Second Messenger Systems/drug effects Sorting Nexins/antagonists & inhibitors/genetics/metabolism Tissue Culture Techniques Venoms/pharmacology Dewey 617 57 Département de chirurgie 222 false 357 La transplantation d'îlots de Langerhans 623 Diabetes 67 3 afd9ad38-66ea-4014-8f89-3c12ddd10aeb Article (Published version) Public 385.full.pdf 3314767 application/pdf OA OTHER 5d1a7ee1-57b8-4a22-babd-9ee6536ffa56 Supplemental data Public DB170639SupplementaryData.pdf 1514244 application/pdf OA OTHER openAccess Faculté de médecine / Section de médecine clinique / Département de chirurgie

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A Targeted RNAi Screen Identifies Endocytic Trafficking Factors That Control GLP-1 Receptor Signaling in Pancreatic β-Cells	Diabetes			2018	457	428

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Rutter, Guy Allen