Human scavenger receptor class B type II (SR-BII) and cellular cholesterol efflux.
Although studies in recombinant cells indicate that scavenger receptor class B, type I (SR-BI) can promote cholesterol efflux, investigations in transgenic mice overexpressing or deficient in SR-BI endorse its physiological function as selectively sequestering cholesteryl esters from high-density lipoproteins (HDLs). Less clear is the role of SR-BII, a splice variant of the SR-B gene that differs only in the C-terminal cytoplasmic domain. Here, we identify several putative signalling motifs in the C-terminus of human SR-BII, which are absent from SR-BI, and hypothesize that these motifs interact with signalling molecules to mobilize stored cholesteryl esters and/or promote the efflux of intracellular free cholesterol. 'Pull-down' assays using a panel of tagged SH3 (Src homology 3) domains showed that cytoplasmic SR-BII, but not cytoplasmic SR-BI, bound the SH3 domain of phospholipase C-gamma1; this interaction was not, however, detected under more physiological conditions. Specific anti-peptide antisera identified SR-BII in human monocyte/macrophage THP-1 cells and, in recombinant cells, revealed receptor localization to caveolae, a plasma membrane microdomain that concentrates signal-transducer molecules and acts as a conduit for cholesterol flux between cells and lipoproteins. Consistent with its caveolar localization, expression of human SR-BII in recombinant Chinese hamster ovary cells (CHO-SR-BII) was associated with increased HDL-mediated cholesterol efflux. Nevertheless, when CHO-SR-BII cells were pre-loaded with cholesteryl [(3)H]oleate and incubated with HDL, cholesteryl ester stores were not reduced compared with control cells. We conclude that although human SR-BII is expressed by macrophages, contains cytoplasmic signalling motifs and localizes to caveolae, its ability to stimulate cholesterol efflux does not reflect enhanced hydrolysis of stored cholesteryl esters.
Mulcahy
Jane V
JV
Department of Medicine, Royal Free, University College Medical School, University College London, Royal Free Campus, London NW3 2PF, U.K.
Riddell
Dave R
DR
Owen
James S
JS
D000595:Amino Acid Sequence; D000818:Animals; D018955:CD36 Antigens / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D016466:CHO Cells; D006528:Carcinoma, Hepatocellular / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D051242:Caveolin 1; D022461:Caveolins / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism*; D002788:Cholesterol Esters / Q000378:metabolism; D006224:Cricetinae; D003593:Cytoplasm / Q000737:chemistry; D006801:Humans; D008113:Liver Neoplasms / Q000150:complications / Q000378:metabolism / Q000473:pathology; D051907:Lysosomal Membrane Proteins; D008264:Macrophages / Q000737:chemistry / Q000378:metabolism; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D009000:Monocytes / Q000737:chemistry / Q000378:metabolism; D010455:Peptides / Q000502:physiology; D011233:Precipitin Tests; D017434:Protein Structure, Tertiary / Q000502:physiology; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D051122:Scavenger Receptors, Class B; D012795:Sialoglycoproteins; D015398:Signal Transduction / Q000502:physiology
D018955:CD36 Antigens; D051242:Caveolin 1; D022461:Caveolins; D002788:Cholesterol Esters; D051907:Lysosomal Membrane Proteins; D008565:Membrane Proteins; D010455:Peptides; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; C074299:SCARB2 protein, human; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D012795:Sialoglycoproteins; D002784:Cholesterol