Scavenger receptor SR-BI
SR-BI or CLA-1 (CD36 and LIMPII Analogous-1) is a 509 amino acid glycoprotein with a large extracellular loop anchored to the plasma membrane at both the N- and C- termini by transmembrane domains with short extensions into the cytoplasm (55). SR-BI is involved in bidirectional cholesterol transport at the cell membrane and is a multiligand receptor as it can bind both native high-density lipoprotein (HDL) and low density lipoproteins (LDL) as well as modified lipoproteins such as oxidized LDL (oxLDL). SR-BI is highly expressed in liver and steroidogenic tissues (55) as well as human monocyte-derived dendritic cells but not on any other peripheral blood mononuclear cells (56). Furthermore, SR-BI and its splicing variant SR-BII, have been found to mediate binding and uptake of a broad range of bacteria into nonphagocytic human epithelial cells overexpressing SR-BI and SR-BII (57, 58) suggesting that class B scavenger receptors may serve as pattern recognition receptors for bacteria. Cross-linking studies using recombinant C-terminally truncated HCV envelope glycoprotein E2 isolated SR-BI on HepG2 cells as a cell surface protein binding HCV envelope glycoprotein E2 (24). SR-BI recognition by HCV E2 required the hypervariable region HVR-1 (24). Moreover, antibodies directed against cell surface expressed SR-BI inhibited binding of recombinant envelope glycoproteins and HCV-like particles to primary hepatocytes (15) as well as HCVpp entry (22, 59, 60). In addition, it has been shown that physiological SR-BI ligands, such as HDL or oxLDL, can modulate HCV infection: HDL and oxLDL have been shown to enhance and inhibit HCVpp entry, respectively (61-63), whereas both HDL and LDL inhibited HCV replication in human hepatocytes infected with serum-derived HCV (64). These results suggest the existence of a complex interplay between lipoproteins, SR-BI and HCV envelope glycoproteins for HCV entry. Most recently, the important role of SR-BI in productive HCV infection has been confirmed using the HCVcc system. Overexpression of SR-BI and SR-BII was able to increase HCVcc infectivity (36) while down-regulation of this receptor by SR-BI specific siRNA markedly reduced the susceptibility of human hepatoma cells to HCVcc infection (Zeisel MB, Schnober EK, Haberstroh A, Lavillette D, Cosset FL, Wakita T, Jaeck D, Royer C, Schuster C, Stoll-Keller F, Blum H, Barth H, Baumert TF. 13th International Meeting on Hepatitis C Virus & Related Viruses 2006, Cairns, Australia). Moreover, anti-SR-BI antibodies directed against epitopes of the SR-BI extracellular loop specifically inhibited HCVcc infection and kinetic studies demonstrated that SR-BI acts predominately following binding of HCV at an entry step occurring at a similar time point as CD81-HCV interaction (38).
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