title: BAG3 regulates formation of the SNARE complex and insulin secretion.
abstract: Insulin release in response to glucose stimulation requires exocytosis of insulin-containing granules. Glucose stimulation of beta cells leads to focal adhesion kinase (FAK) phosphorylation, which acts on the Rho family proteins (Rho, Rac and Cdc42) that direct F-actin remodeling. This process requires docking and fusion of secretory vesicles to the release sites at the plasma membrane and is a complex mechanism that is mediated by SNAREs. This transiently disrupts the F-actin barrier and allows the redistribution of the insulin-containing granules to more peripheral regions of the β cell, hence facilitating insulin secretion. In this manuscript, we show for the first time that BAG3 plays an important role in this process. We show that BAG3 downregulation results in increased insulin secretion in response to glucose stimulation and in disruption of the F-actin network. Moreover, we show that BAG3 binds to SNAP-25 and syntaxin-1, two components of the t-SNARE complex preventing the interaction between SNAP-25 and syntaxin-1. Upon glucose stimulation BAG3 is phosphorylated by FAK and dissociates from SNAP-25 allowing the formation of the SNARE complex, destabilization of the F-actin network and insulin release.
authors.affiliation: Department of Pharmacy, University of Salerno, via Giovanni Paolo II, 132, Fisciano, SA, Italy.
authors.forename: V
authors.identifier: 0000000178264725
authors.initials: V
authors.lastname: Iorio
authors.affiliation: 1] Department of Pharmacy, University of Salerno, via Giovanni Paolo II, 132, Fisciano, SA, Italy [2] BIOUNIVERSA S.r.l., University of Salerno, via Giovanni Paolo II, 132, Fisciano, SA, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Festa
authors.affiliation: 1] Department of Pharmacy, University of Salerno, via Giovanni Paolo II, 132, Fisciano, SA, Italy [2] BIOUNIVERSA S.r.l., University of Salerno, via Giovanni Paolo II, 132, Fisciano, SA, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Rosati
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, CNRS UMR5535, Montpellier, France.
authors.forename: M
authors.initials: M
authors.lastname: Hahne
authors.affiliation: Department of Clinical Sciences, University of Rome Sapienza, Rome, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Tiberti
authors.affiliation: Department of Medicine and Surgery, University of Salerno, Via S. Allende, Baronissi, SA, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Capunzo
authors.affiliation: 1] BIOUNIVERSA S.r.l., University of Salerno, via Giovanni Paolo II, 132, Fisciano, SA, Italy [2] Department of Experimental and Clinical Sciences, University G. D'Annunzio and Fondazione G. D'Annunzio, Ce.S.I., Chieti, Italy.
authors.forename: V
authors.initials: V
authors.lastname: De Laurenzi
authors.affiliation: 1] BIOUNIVERSA S.r.l., University of Salerno, via Giovanni Paolo II, 132, Fisciano, SA, Italy [2] Department of Medicine and Surgery, University of Salerno, Via S. Allende, Baronissi, SA, Italy.
authors.forename: M C
authors.initials: MC
authors.lastname: Turco
mesh_terms: D000199:Actins / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis* / Q000378:metabolism; D000328:Adult; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis* / Q000378:metabolism; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000008:administration & dosage; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010179:Pancreas / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D050600:SNARE Proteins / Q000235:genetics / Q000378:metabolism; D050825:Synaptosomal-Associated Protein 25 / Q000235:genetics / Q000378:metabolism*; D050827:Syntaxin 1 / Q000378:metabolism; D046888:Tissue Array Analysis
chemical_list: D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C414431:BAG3 protein, human; D007328:Insulin; C494208:SNAP25 protein, human; D050600:SNARE Proteins; D050825:Synaptosomal-Associated Protein 25; D050827:Syntaxin 1; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D005947:Glucose