title: Control of plasma membrane lipid homeostasis by the extended synaptotagmins.
abstract: Acute metabolic changes in plasma membrane (PM) lipids, such as those mediating signalling reactions, are rapidly compensated by homeostatic responses whose molecular basis is poorly understood. Here we show that the extended synaptotagmins (E-Syts), endoplasmic reticulum (ER) proteins that function as PtdIns(4,5)P2- and Ca(2+)-regulated tethers to the PM, participate in these responses. E-Syts transfer glycerolipids between bilayers in vitro, and this transfer requires Ca(2+) and their lipid-harbouring SMP domain. Genome-edited cells lacking E-Syts do not exhibit abnormalities in the major glycerolipids at rest, but exhibit enhanced and sustained accumulation of PM diacylglycerol following PtdIns(4,5)P2 hydrolysis by PLC activation, which can be rescued by expression of E-Syt1, but not by mutant E-Syt1 lacking the SMP domain. The formation of E-Syt-dependent ER-PM tethers in response to stimuli that cleave PtdIns(4,5)P2 and elevate Ca(2+) may help reverse accumulation of diacylglycerol in the PM by transferring it to the ER for metabolic recycling.
authors.affiliation: Department of Neuroscience, Yale University School of Medicine, New Haven, Connecticut 06510, USA.|Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.|Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06510, USA.|Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, Connecticut 06510, USA.|Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Saheki
authors.affiliation: Department of Neuroscience, Yale University School of Medicine, New Haven, Connecticut 06510, USA.|Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.|Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06510, USA.|Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, Connecticut 06510, USA.|Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Bian
authors.affiliation: Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Curtis M
authors.initials: CM
authors.lastname: Schauder
authors.affiliation: Department of Neuroscience, Yale University School of Medicine, New Haven, Connecticut 06510, USA.|Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.|Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06510, USA.|Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, Connecticut 06510, USA.|Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Yujin
authors.initials: Y
authors.lastname: Sawaki
authors.affiliation: Lipotype GmbH, Am Tatzberg 47-49, 01307 Dresden, Germany.
authors.forename: Michal A
authors.initials: MA
authors.lastname: Surma
authors.affiliation: Lipotype GmbH, Am Tatzberg 47-49, 01307 Dresden, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Klose
authors.affiliation: Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.|Laboratoire de Physique Statistique, Ecole Normale Supérieure de Paris, Université Pierre et Marie Curie, Université Paris Diderot, Centre National de la Recherche Scientifique, UMR 8550, 24 rue Lhomond, 75005 Paris, France.
authors.forename: Frederic
authors.initials: F
authors.lastname: Pincet
authors.affiliation: Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Karin M
authors.initials: KM
authors.lastname: Reinisch
authors.affiliation: Department of Neuroscience, Yale University School of Medicine, New Haven, Connecticut 06510, USA.|Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.|Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06510, USA.|Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, Connecticut 06510, USA.|Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Pietro
authors.initials: P
authors.lastname: De Camilli
mesh_terms: D001692:Biological Transport; D064113:CRISPR-Cas Systems; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D004075:Diglycerides / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004789:Enzyme Activation; D055786:Gene Knockout Techniques; D006367:HeLa Cells; D006706:Homeostasis; D006801:Humans; D008563:Membrane Lipids / Q000378:metabolism*; D050857:Synaptotagmins / Q000378:metabolism*; D000069896:Transcription Activator-Like Effector Nucleases / Q000378:metabolism; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D004075:Diglycerides; D008563:Membrane Lipids; C030363:lipid transfer protein; D050857:Synaptotagmins; D000069896:Transcription Activator-Like Effector Nucleases; D010738:Type C Phospholipases; D002118:Calcium