title: Caveolin-1 interacts with ATP binding cassette transporter G1 (ABCG1) and regulates ABCG1-mediated cholesterol efflux.
abstract: ATP-binding cassette transporter G1 (ABCG1) plays an important role in macrophage reverse cholesterol transport in vivo by promoting cholesterol efflux onto lipidated apoA-I. However, the underlying mechanism is unclear. Here, we found that ABCG1 co-immunoprecipitated with caveolin-1 (CAV1) but not with flotillin-1 and -2. Knockdown of CAV1 expression using siRNAs significantly reduced ABCG1-mediated cholesterol efflux without detectable effect on ABCA1-mediated cholesterol efflux. Disruption of the putative CAV1 binding site in ABCG1, through replacement of tyrosine residues at positions 487 and 489 or at positions 494 and 495 with alanine (Y487AY489A and Y494AY495A), impaired the interaction of ABCG1 with CAV1 and significantly decreased ABCG1-mediated cholesterol efflux. The substitution of Tyr494 and Tyr495 with Phe or Trp that resulted in an intact CAV1 binding site had no effect. Furthermore, Y494AY495A affected trafficking of ABCG1 to the cell surface. The mutant protein is mainly located intracellularly. Finally, we found that CAV1 co-immunoprecipitated with ABCG1 and regulated cholesterol efflux to reconstituted HDL in THP-1-derived macrophages upon the liver X receptor agonist treatment. These findings indicate that CAV1 interacts with ABCG1 and regulates ABCG1-mediated cholesterol efflux.
authors.affiliation: Departments of Pediatrics and Biochemistry, The Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, AB T6G 2S2, Canada.
authors.forename: Hong-Mei
authors.initials: HM
authors.lastname: Gu
authors.affiliation: Departments of Pediatrics and Biochemistry, The Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, AB T6G 2S2, Canada.
authors.forename: Fa-Qi
authors.initials: FQ
authors.lastname: Wang
authors.affiliation: Departments of Pediatrics and Biochemistry, The Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, AB T6G 2S2, Canada. Electronic address: dzhang@ualberta.ca.
authors.forename: Da-Wei
authors.initials: DW
authors.lastname: Zhang
mesh_terms: D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D001692:Biological Transport / Q000235:genetics; D051242:Caveolin 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000071518:Liver X Receptors; D008565:Membrane Proteins / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000037:antagonists & inhibitors; D011485:Protein Binding / Q000235:genetics*; D034741:RNA, Small Interfering
chemical_list: C419353:ABCG1 protein, human; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D051242:Caveolin 1; D000071518:Liver X Receptors; D008565:Membrane Proteins; D057093:Orphan Nuclear Receptors; D034741:RNA, Small Interfering; C106354:flotillins; D002784:Cholesterol
keywords: ABC transporter; Caveolin; Cholesterol efflux