Stabilization of caveolin-1 by cellular cholesterol and scavenger receptor class B type I.
Caveolae are 50-100 nm plasma membrane invaginations, which function in cell signaling, in transcytosis, and in regulating cellular cholesterol homeostasis. These subcompartments of the plasma membrane are characterized by the presence of caveolin proteins. Recent studies have indicated that caveolae may be involved in the regulation of cellular cholesterol efflux to high-density lipoproteins (HDL), as well as selective cholesteryl ester uptake mediated by scavenger receptor class B type I (SR-BI). In the present studies, we show that caveolin-1 expression in HEK-293T cells has no effect on SR-BI-mediated cellular cholesterol efflux to reconstituted HDL. However, SR-BI-mediated selective cholesteryl ester uptake is significantly inhibited by caveolin-1. Interestingly, we also found that SR-BI, but not CD36, can induce the dramatic stabilization of the caveolin-1 protein, independently of its transcriptional control. On the other hand, caveolin-1 has little effect on SR-BI stability, but clearly increases CD36 stability. Since SR-BI expression has been shown to increase cellular cholesterol levels, we next examined the effect of cholesterol itself on caveolin-1 stabilization and localization. When cells were loaded with cholesterol, we observed the dramatic stabilization of caveolin-1 with significant clustering of caveolin-1 at the cell surface. In addition, a palmitoylation-deficient caveolin-1 mutant was still responsive to cholesterol-induced stabilization, indicating that palmitoylation of caveolin-1 is not required for the cholesterol-induced stabilization of caveolin-1. These results suggest an important role for cholesterol and SR-BI in the regulation of caveolin functioning, especially in cell types such as endothelial cells and macrophages, which can be dramatically affected by changes in their cholesterol content during the development of atherosclerosis.
Frank
Philippe G
PG
Department of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
Marcel
Yves L
YL
Connelly
Margery A
MA
Lublin
Douglas M
DM
Franklin
Vivian
V
Williams
David L
DL
Lisanti
Michael P
MP
D000818:Animals; D018955:CD36 Antigens / Q000096:biosynthesis / Q000502:physiology*; D019556:COS Cells; D051242:Caveolin 1; D022461:Caveolins / Q000096:biosynthesis / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism / Q000502:physiology*; D002788:Cholesterol Esters / Q000037:antagonists & inhibitors / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology; D006801:Humans; D008565:Membrane Proteins; D018613:Microscopy, Confocal; D019308:Palmitic Acid / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D051122:Scavenger Receptors, Class B; D013347:Subcellular Fractions / Q000737:chemistry / Q000378:metabolism; D014162:Transfection
C495540:CAV1 protein, human; D018955:CD36 Antigens; D051242:Caveolin 1; D022461:Caveolins; D002788:Cholesterol Esters; D008565:Membrane Proteins; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; C495124:SCARB1 protein, human; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D019308:Palmitic Acid; D002784:Cholesterol