β-Cell Insulin Secretion Requires the Ubiquitin Ligase COP1

• Published in: Cell 2015-12, Vol.163 (6), p.1457-1467
• Main Authors: Suriben, Rowena, Kaihara, Kelly A., Paolino, Magdalena, Reichelt, Mike, Kummerfeld, Sarah K., Modrusan, Zora, Dugger, Debra L., Newton, Kim, Sagolla, Meredith, Webster, Joshua D., Liu, Jinfeng, Hebrok, Matthias, Dixit, Vishva M.
• Format: Article
• Language: English
• Subjects: Animals; blood glucose; diabetes; Diabetes Mellitus - metabolism; DNA-Binding Proteins - metabolism; Exocytosis; Gene Deletion; Glucose - metabolism; Humans; Hyperglycemia - metabolism; insulin; Insulin - metabolism; Insulin Secretion; Insulin-Secreting Cells - metabolism; Mice; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; pathophysiology; Proto-Oncogene Proteins c-ets - metabolism; Transcription Factors - metabolism; ubiquitin-protein ligase; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2015.10.076

A variety of signals finely tune insulin secretion by pancreatic β cells to prevent both hyper-and hypoglycemic states. Here, we show that post-translational regulation of the transcription factors ETV1, ETV4, and ETV5 by the ubiquitin ligase COP1 (also called RFWD2) in β cells is critical for insulin secretion. Mice lacking COP1 in β cells developed diabetes due to insulin granule docking defects that were fully rescued by genetic deletion of Etv1, Etv4, and Etv5. Genes regulated by ETV1, ETV4, or ETV5 in the absence of mouse COP1 were enriched in human diabetes-associated genes, suggesting that they also influence human β-cell pathophysiology. In normal β cells, ETV4 was stabilized upon membrane depolarization and limited insulin secretion under hyperglycemic conditions. Collectively, our data reveal that ETVs negatively regulate insulin secretion for the maintenance of normoglycemia. [Display omitted] •Loss of COP1 in β cells caused insulin secretion defects and hyperglycemia•Deletion of transcription factors ETV1, ETV4, and ETV5 rescued COP1 phenotypes•ETV-dependent genes were significantly enriched in human diabetes and obesity GWAS•ETV transcription factors limited insulin secretion under hyperglycemic conditions In adult pancreatic β cells, the post-translational regulation of the transcription factors ETV1, ETV4, and ETV5 by the ubiquitin ligase COP1 is critical for insulin secretion and the maintenance of normal glucose homeostasis. Dysregulation of this axis leads to the mis-expression of several ETV-target genes that are linked to diabetes and obesity.