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.
Department of Medicine, Royal Free, University College Medical School, University College London, Royal Free Campus, London NW3 2PF, U.K.
Jane V
JV
Mulcahy
Dave R
DR
Riddell
James S
JS
Owen
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