title: Scavenger receptor class B type I is a plasma membrane cholesterol sensor.
abstract: BACKGROUND
  Signal initiation by the high-density lipoprotein (HDL) receptor scavenger receptor class B, type I (SR-BI), which is important to actions of HDL on endothelium and other processes, requires cholesterol efflux and the C-terminal transmembrane domain. The C-terminal transmembrane domain uniquely interacts with plasma membrane (PM) cholesterol.
  
  
  OBJECTIVE
  The molecular basis and functional significance of SR-BI interaction with PM cholesterol are unknown. We tested the hypotheses that the interaction is required for SR-BI signaling, and that it enables SR-BI to serve as a PM cholesterol sensor.
  
  
  RESULTS
  In studies performed in COS-M6 cells, mutation of a highly conserved C-terminal transmembrane domain glutamine to alanine (SR-BI-Q445A) decreased PM cholesterol interaction with the receptor by 71% without altering HDL binding or cholesterol uptake or efflux, and it yielded a receptor incapable of HDL-induced signaling. Signaling prompted by cholesterol efflux to methyl-β-cyclodextrin also was prevented, indicating that PM cholesterol interaction with the receptor enables it to serve as a PM cholesterol sensor. Using SR-BI-Q445A, we further demonstrated that PM cholesterol sensing by SR-BI does not influence SR-BI-mediated reverse cholesterol transport to the liver in mice. However, the PM cholesterol sensing does underlie apolipoprotein B intracellular trafficking in response to postprandial micelles or methyl-β-cyclodextrin in cultured enterocytes, and it is required for HDL activation of endothelial NO synthase and migration in cultured endothelial cells and HDL-induced angiogenesis in vivo.
  
  
  CONCLUSIONS
  Through interaction with PM cholesterol, SR-BI serves as a PM cholesterol sensor, and the resulting intracellular signaling governs processes in both enterocytes and endothelial cells.
authors.affiliation: Department of Pediatrics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA.
authors.forename: Sonika
authors.initials: S
authors.lastname: Saddar
authors.forename: Véronique
authors.initials: V
authors.lastname: Carriere
authors.forename: Wan-Ru
authors.initials: WR
authors.lastname: Lee
authors.forename: Keiji
authors.initials: K
authors.lastname: Tanigaki
authors.forename: Ivan S
authors.initials: IS
authors.lastname: Yuhanna
authors.forename: Sajesh
authors.initials: S
authors.lastname: Parathath
authors.forename: Etienne
authors.initials: E
authors.lastname: Morel
authors.forename: Manya
authors.initials: M
authors.lastname: Warrier
authors.forename: Janet K
authors.initials: JK
authors.lastname: Sawyer
authors.forename: Robert D
authors.initials: RD
authors.lastname: Gerard
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Temel
authors.forename: J Mark
authors.initials: JM
authors.lastname: Brown
authors.forename: Margery
authors.initials: M
authors.lastname: Connelly
authors.forename: Chieko
authors.initials: C
authors.lastname: Mineo
authors.forename: Philip W
authors.initials: PW
authors.lastname: Shaul
mesh_terms: D000409:Alanine; D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism; D018938:Caco-2 Cells; D002417:Cattle; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D020895:Enterocytes / Q000187:drug effects / Q000378:metabolism*; D005973:Glutamine; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D018919:Neovascularization, Physiologic; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051122:Scavenger Receptors, Class B / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D047392:beta-Cyclodextrins / Q000494:pharmacology
chemical_list: D001055:Apolipoproteins B; D008076:Cholesterol, HDL; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C514896:PDZK1 protein, mouse; C495124:SCARB1 protein, human; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; D005973:Glutamine; D002784:Cholesterol; D052250:Nitric Oxide Synthase Type III; D000409:Alanine