title: ATP-binding cassette transporters and sterol O-acyltransferases interact at membrane microdomains to modulate sterol uptake and esterification.
abstract: A key component of eukaryotic lipid homeostasis is the esterification of sterols with fatty acids by sterol O-acyltransferases (SOATs). The esterification reactions are allosterically activated by their sterol substrates, the majority of which accumulate at the plasma membrane. We demonstrate that in yeast, sterol transport from the plasma membrane to the site of esterification is associated with the physical interaction of the major SOAT, acyl-coenzyme A:cholesterol acyltransferase (ACAT)-related enzyme (Are)2p, with 2 plasma membrane ATP-binding cassette (ABC) transporters: Aus1p and Pdr11p. Are2p, Aus1p, and Pdr11p, unlike the minor acyltransferase, Are1p, colocalize to sterol and sphingolipid-enriched, detergent-resistant microdomains (DRMs). Deletion of either ABC transporter results in Are2p relocalization to detergent-soluble membrane domains and a significant decrease (53-36%) in esterification of exogenous sterol. Similarly, in murine tissues, the SOAT1/Acat1 enzyme and activity localize to DRMs. This subcellular localization is diminished upon deletion of murine ABC transporters, such as Abcg1, which itself is DRM associated. We propose that the close proximity of sterol esterification and transport proteins to each other combined with their residence in lipid-enriched membrane microdomains facilitates rapid, high-capacity sterol transport and esterification, obviating any requirement for soluble intermediary proteins.
authors.affiliation: *Institute of Human Nutrition, Department of Neurology, **Department of Genetics and Development, and Department of Pediatrics, Columbia University Medical Center, New York, New York, USA; Department of Biological Sciences and Department of Chemistry, Columbia University, New York, New York, USA; Donnelly Center for Cellular and Biomolecular Research, Toronto, Ontario, Canada; Institute of Molecular Biosciences, BioTechMed Graz, University of Graz, Graz, Austria; Department of Biology, Providence College, Providence, Rhode Island, USA; and Marine Biological Laboratory, Woods Hole, Massachusetts, USA.
authors.forename: Sonia
authors.initials: S
authors.lastname: Gulati
authors.affiliation: *Institute of Human Nutrition, Department of Neurology, **Department of Genetics and Development, and Department of Pediatrics, Columbia University Medical Center, New York, New York, USA; Department of Biological Sciences and Department of Chemistry, Columbia University, New York, New York, USA; Donnelly Center for Cellular and Biomolecular Research, Toronto, Ontario, Canada; Institute of Molecular Biosciences, BioTechMed Graz, University of Graz, Graz, Austria; Department of Biology, Providence College, Providence, Rhode Island, USA; and Marine Biological Laboratory, Woods Hole, Massachusetts, USA.
authors.forename: Dina
authors.initials: D
authors.lastname: Balderes
authors.affiliation: *Institute of Human Nutrition, Department of Neurology, **Department of Genetics and Development, and Department of Pediatrics, Columbia University Medical Center, New York, New York, USA; Department of Biological Sciences and Department of Chemistry, Columbia University, New York, New York, USA; Donnelly Center for Cellular and Biomolecular Research, Toronto, Ontario, Canada; Institute of Molecular Biosciences, BioTechMed Graz, University of Graz, Graz, Austria; Department of Biology, Providence College, Providence, Rhode Island, USA; and Marine Biological Laboratory, Woods Hole, Massachusetts, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Kim
authors.affiliation: *Institute of Human Nutrition, Department of Neurology, **Department of Genetics and Development, and Department of Pediatrics, Columbia University Medical Center, New York, New York, USA; Department of Biological Sciences and Department of Chemistry, Columbia University, New York, New York, USA; Donnelly Center for Cellular and Biomolecular Research, Toronto, Ontario, Canada; Institute of Molecular Biosciences, BioTechMed Graz, University of Graz, Graz, Austria; Department of Biology, Providence College, Providence, Rhode Island, USA; and Marine Biological Laboratory, Woods Hole, Massachusetts, USA.
authors.forename: Zhongmin A
authors.initials: ZA
authors.lastname: Guo
authors.affiliation: *Institute of Human Nutrition, Department of Neurology, **Department of Genetics and Development, and Department of Pediatrics, Columbia University Medical Center, New York, New York, USA; Department of Biological Sciences and Department of Chemistry, Columbia University, New York, New York, USA; Donnelly Center for Cellular and Biomolecular Research, Toronto, Ontario, Canada; Institute of Molecular Biosciences, BioTechMed Graz, University of Graz, Graz, Austria; Department of Biology, Providence College, Providence, Rhode Island, USA; and Marine Biological Laboratory, Woods Hole, Massachusetts, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Wilcox
authors.affiliation: *Institute of Human Nutrition, Department of Neurology, **Department of Genetics and Development, and Department of Pediatrics, Columbia University Medical Center, New York, New York, USA; Department of Biological Sciences and Department of Chemistry, Columbia University, New York, New York, USA; Donnelly Center for Cellular and Biomolecular Research, Toronto, Ontario, Canada; Institute of Molecular Biosciences, BioTechMed Graz, University of Graz, Graz, Austria; Department of Biology, Providence College, Providence, Rhode Island, USA; and Marine Biological Laboratory, Woods Hole, Massachusetts, USA.
authors.forename: Estela
authors.initials: E
authors.lastname: Area-Gomez
authors.affiliation: *Institute of Human Nutrition, Department of Neurology, **Department of Genetics and Development, and Department of Pediatrics, Columbia University Medical Center, New York, New York, USA; Department of Biological Sciences and Department of Chemistry, Columbia University, New York, New York, USA; Donnelly Center for Cellular and Biomolecular Research, Toronto, Ontario, Canada; Institute of Molecular Biosciences, BioTechMed Graz, University of Graz, Graz, Austria; Department of Biology, Providence College, Providence, Rhode Island, USA; and Marine Biological Laboratory, Woods Hole, Massachusetts, USA.
authors.forename: Jamie
authors.initials: J
authors.lastname: Snider
authors.affiliation: *Institute of Human Nutrition, Department of Neurology, **Department of Genetics and Development, and Department of Pediatrics, Columbia University Medical Center, New York, New York, USA; Department of Biological Sciences and Department of Chemistry, Columbia University, New York, New York, USA; Donnelly Center for Cellular and Biomolecular Research, Toronto, Ontario, Canada; Institute of Molecular Biosciences, BioTechMed Graz, University of Graz, Graz, Austria; Department of Biology, Providence College, Providence, Rhode Island, USA; and Marine Biological Laboratory, Woods Hole, Massachusetts, USA.
authors.forename: Heimo
authors.initials: H
authors.lastname: Wolinski
authors.affiliation: *Institute of Human Nutrition, Department of Neurology, **Department of Genetics and Development, and Department of Pediatrics, Columbia University Medical Center, New York, New York, USA; Department of Biological Sciences and Department of Chemistry, Columbia University, New York, New York, USA; Donnelly Center for Cellular and Biomolecular Research, Toronto, Ontario, Canada; Institute of Molecular Biosciences, BioTechMed Graz, University of Graz, Graz, Austria; Department of Biology, Providence College, Providence, Rhode Island, USA; and Marine Biological Laboratory, Woods Hole, Massachusetts, USA.
authors.forename: Igor
authors.initials: I
authors.lastname: Stagljar
authors.affiliation: *Institute of Human Nutrition, Department of Neurology, **Department of Genetics and Development, and Department of Pediatrics, Columbia University Medical Center, New York, New York, USA; Department of Biological Sciences and Department of Chemistry, Columbia University, New York, New York, USA; Donnelly Center for Cellular and Biomolecular Research, Toronto, Ontario, Canada; Institute of Molecular Biosciences, BioTechMed Graz, University of Graz, Graz, Austria; Department of Biology, Providence College, Providence, Rhode Island, USA; and Marine Biological Laboratory, Woods Hole, Massachusetts, USA.
authors.forename: Juliana T
authors.initials: JT
authors.lastname: Granato
authors.affiliation: *Institute of Human Nutrition, Department of Neurology, **Department of Genetics and Development, and Department of Pediatrics, Columbia University Medical Center, New York, New York, USA; Department of Biological Sciences and Department of Chemistry, Columbia University, New York, New York, USA; Donnelly Center for Cellular and Biomolecular Research, Toronto, Ontario, Canada; Institute of Molecular Biosciences, BioTechMed Graz, University of Graz, Graz, Austria; Department of Biology, Providence College, Providence, Rhode Island, USA; and Marine Biological Laboratory, Woods Hole, Massachusetts, USA.
authors.forename: Kelly V
authors.initials: KV
authors.lastname: Ruggles
authors.affiliation: *Institute of Human Nutrition, Department of Neurology, **Department of Genetics and Development, and Department of Pediatrics, Columbia University Medical Center, New York, New York, USA; Department of Biological Sciences and Department of Chemistry, Columbia University, New York, New York, USA; Donnelly Center for Cellular and Biomolecular Research, Toronto, Ontario, Canada; Institute of Molecular Biosciences, BioTechMed Graz, University of Graz, Graz, Austria; Department of Biology, Providence College, Providence, Rhode Island, USA; and Marine Biological Laboratory, Woods Hole, Massachusetts, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: DeGiorgis
authors.affiliation: *Institute of Human Nutrition, Department of Neurology, **Department of Genetics and Development, and Department of Pediatrics, Columbia University Medical Center, New York, New York, USA; Department of Biological Sciences and Department of Chemistry, Columbia University, New York, New York, USA; Donnelly Center for Cellular and Biomolecular Research, Toronto, Ontario, Canada; Institute of Molecular Biosciences, BioTechMed Graz, University of Graz, Graz, Austria; Department of Biology, Providence College, Providence, Rhode Island, USA; and Marine Biological Laboratory, Woods Hole, Massachusetts, USA.
authors.forename: Sepp D
authors.initials: SD
authors.lastname: Kohlwein
authors.affiliation: *Institute of Human Nutrition, Department of Neurology, **Department of Genetics and Development, and Department of Pediatrics, Columbia University Medical Center, New York, New York, USA; Department of Biological Sciences and Department of Chemistry, Columbia University, New York, New York, USA; Donnelly Center for Cellular and Biomolecular Research, Toronto, Ontario, Canada; Institute of Molecular Biosciences, BioTechMed Graz, University of Graz, Graz, Austria; Department of Biology, Providence College, Providence, Rhode Island, USA; and Marine Biological Laboratory, Woods Hole, Massachusetts, USA.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Schon
authors.affiliation: *Institute of Human Nutrition, Department of Neurology, **Department of Genetics and Development, and Department of Pediatrics, Columbia University Medical Center, New York, New York, USA; Department of Biological Sciences and Department of Chemistry, Columbia University, New York, New York, USA; Donnelly Center for Cellular and Biomolecular Research, Toronto, Ontario, Canada; Institute of Molecular Biosciences, BioTechMed Graz, University of Graz, Graz, Austria; Department of Biology, Providence College, Providence, Rhode Island, USA; and Marine Biological Laboratory, Woods Hole, Massachusetts, USA sls37@columbia.edu.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Sturley
mesh_terms: D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004951:Esterification / Q000502:physiology; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism; D021962:Membrane Microdomains / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D002785:Sterol O-Acyltransferase / Q000235:genetics / Q000378:metabolism*; D013261:Sterols / Q000378:metabolism*
chemical_list: C487540:ABCG1 protein, mouse; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; C466994:AUS1 protein, S cerevisiae; D008074:Lipoproteins; C466995:PDR11 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D013261:Sterols; C543388:ARE2 protein, S cerevisiae; D002785:Sterol O-Acyltransferase
keywords: ABC transporter; cholesteryl ester; lipid droplet; sterol transport