title: β-Cell Insulin Secretion Requires the Ubiquitin Ligase COP1.
abstract: 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.
authors.affiliation: Department of Physiological Chemistry, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Rowena
authors.initials: R
authors.lastname: Suriben
authors.affiliation: Diabetes Center, University of California, San Francisco, San Francisco, CA 94143 USA.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Kaihara
authors.affiliation: Department of Physiological Chemistry, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Paolino
authors.affiliation: Department of Pathology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Mike
authors.initials: M
authors.lastname: Reichelt
authors.affiliation: Department of Bioinformatics and Computational Biology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Kummerfeld
authors.affiliation: Department of Molecular Biology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Zora
authors.initials: Z
authors.lastname: Modrusan
authors.affiliation: Department of Physiological Chemistry, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Debra L
authors.initials: DL
authors.lastname: Dugger
authors.affiliation: Department of Physiological Chemistry, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Kim
authors.initials: K
authors.lastname: Newton
authors.affiliation: Department of Pathology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Meredith
authors.initials: M
authors.lastname: Sagolla
authors.affiliation: Department of Pathology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Webster
authors.affiliation: Department of Bioinformatics and Computational Biology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Liu
authors.affiliation: Diabetes Center, University of California, San Francisco, San Francisco, CA 94143 USA.
authors.forename: Matthias
authors.initials: M
authors.lastname: Hebrok
authors.affiliation: Department of Physiological Chemistry, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: dixit@gene.com.
authors.forename: Vishva M
authors.initials: VM
authors.lastname: Dixit
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism; D003920:Diabetes Mellitus / Q000378:metabolism; D005089:Exocytosis; D017353:Gene Deletion; D005947:Glucose / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D050783:Proto-Oncogene Proteins c-ets / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C490641:Etv1 protein, mouse; C540571:Etv4 protein, mouse; C513242:Etv5 protein, mouse; D007328:Insulin; D009687:Nuclear Proteins; D050783:Proto-Oncogene Proteins c-ets; D014157:Transcription Factors; C065788:transcription factor PEA3; C471982:COP1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D005947:Glucose