title: Lipid transport by TMEM24 at ER-plasma membrane contacts regulates pulsatile insulin secretion.
abstract: Insulin is released by β cells in pulses regulated by calcium and phosphoinositide signaling. Here, we describe how transmembrane protein 24 (TMEM24) helps coordinate these signaling events. We showed that TMEM24 is an endoplasmic reticulum (ER)-anchored membrane protein whose reversible localization to ER-plasma membrane (PM) contacts is governed by phosphorylation and dephosphorylation in response to oscillations in cytosolic calcium. A lipid-binding module in TMEM24 transports the phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] precursor phosphatidylinositol between bilayers, allowing replenishment of PI(4,5)P2hydrolyzed during signaling. In the absence of TMEM24, calcium oscillations are abolished, leading to a defect in triggered insulin release. Our findings implicate direct lipid transport between the ER and the PM in the control of insulin secretion, a process impaired in patients with type II diabetes.
authors.affiliation: Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Joshua A
authors.identifier: 0000-0001-7421-6881
authors.initials: JA
authors.lastname: Lees
authors.affiliation: Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06520, USA.|Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06510, USA.|Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510, USA.|Program in Cellular Neuroscience, Neurodegeneration, and Repair, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Mirko
authors.identifier: 0000-0001-7133-0152
authors.initials: M
authors.lastname: Messa
authors.affiliation: Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06520, USA.|Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06510, USA.|Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510, USA.|Program in Cellular Neuroscience, Neurodegeneration, and Repair, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Elizabeth Wen
authors.identifier: 0000-0002-0365-7337
authors.initials: EW
authors.lastname: Sun
authors.affiliation: Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06520, USA.|Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06510, USA.|Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510, USA.|Program in Cellular Neuroscience, Neurodegeneration, and Repair, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Heather
authors.identifier: 0000-0002-8097-4344
authors.initials: H
authors.lastname: Wheeler
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 117599 Singapore.
authors.forename: Federico
authors.initials: F
authors.lastname: Torta
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 117599 Singapore.
authors.forename: Markus R
authors.identifier: 0000-0001-5447-7881
authors.initials: MR
authors.lastname: Wenk
authors.affiliation: Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06520, USA. pietro.decamilli@yale.edu karin.reinisch@yale.edu.|Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06510, USA.|Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510, USA.|Program in Cellular Neuroscience, Neurodegeneration, and Repair, Yale University School of Medicine, New Haven, CT 06510, USA.|Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Pietro
authors.identifier: 0000-0001-9045-0723
authors.initials: P
authors.lastname: De Camilli
authors.affiliation: Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06520, USA. pietro.decamilli@yale.edu karin.reinisch@yale.edu.
authors.forename: Karin M
authors.identifier: 0000-0001-9140-6150
authors.initials: KM
authors.lastname: Reinisch
mesh_terms: D000818:Animals; D001692:Biological Transport; D019556:COS Cells; D020013:Calcium Signaling; D002462:Cell Membrane / Q000378:metabolism; D002522:Chlorocebus aethiops; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D055786:Gene Knockout Techniques; D006367:HeLa Cells; D006801:Humans; D006868:Hydrolysis; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050356:Lipid Metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D010766:Phosphorylation
chemical_list: C498364:C2CD2L protein, human; D007328:Insulin; D008565:Membrane Proteins; D019269:Phosphatidylinositol 4,5-Diphosphate