title: The mammalian ABC transporter ABCA1 induces lipid-dependent drug sensitivity in yeast.
abstract: ABCA1 belongs to the A class of ABC transporter, which is absent in yeast. ABCA1 elicits lipid translocation at the plasma membrane through yet elusive processes. We successfully expressed the mouse Abca1 gene in Saccharomyces cerevisiae. The cloned ABCA1 distributed at the yeast plasma membrane in stable discrete domains that we name MCA (membrane cluster containing ABCA1) and that do not overlap with the previously identified punctate structures MCC (membrane cluster containing Can1p) and MCP (membrane cluster containing Pma1p). By comparison with a nonfunctional mutant, we demonstrated that ABCA1 elicits specific phenotypes in response to compounds known to interact with membrane lipids, such as papuamide B, amphotericin B and pimaricin. The sensitivity of these novel phenotypes to the genetic modification of the membrane lipid composition was studied by the introduction of the cho1 and lcb1-100 mutations involved respectively in phosphatidylserine or sphingolipid biosynthesis in yeast cells. The results, corroborated by the analysis of equivalent mammalian mutant cell lines, demonstrate that membrane composition, in particular its phosphatidylserine content, influences the function of the transporter. We thus have reconstituted in yeast the essential functions associated to the expression of ABCA1 in mammals and characterized new physiological phenotypes prone to genetic analysis. This article is a part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945-2010).
authors.affiliation: Centre d'Immunologie de Marseille Luminy CNRS INSERM Université de la Méditerranée, Parc Scientifique de Luminy, 13288 Marseille, Cedex 09, France.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Bocer
authors.forename: Ana
authors.initials: A
authors.lastname: Zarubica
authors.forename: Annie
authors.initials: A
authors.lastname: Roussel
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Flis
authors.forename: Tomasz
authors.initials: T
authors.lastname: Trombik
authors.forename: Andre
authors.initials: A
authors.lastname: Goffeau
authors.forename: Stanislaw
authors.initials: S
authors.lastname: Ulaszewski
authors.forename: Giovanna
authors.initials: G
authors.lastname: Chimini
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis* / Q000235:genetics; D000666:Amphotericin B / Q000494:pharmacology*; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D047630:Depsipeptides / Q000494:pharmacology; D015870:Gene Expression; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D010866:Natamycin / Q000494:pharmacology; D010718:Phosphatidylserines / Q000378:metabolism / Q000502:physiology*; D021381:Protein Transport; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D013107:Sphingolipids / Q000378:metabolism / Q000502:physiology
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D000935:Antifungal Agents; D047630:Depsipeptides; D010718:Phosphatidylserines; D011993:Recombinant Fusion Proteins; D013107:Sphingolipids; C474171:papuamide B; D000666:Amphotericin B; D010866:Natamycin