Scavenger receptor class B type I is a plasma membrane cholesterol sensor.

Sonika Saddar, Véronique Carriere, Wan Ru Lee, Keiji Tanigaki, Ivan S. Yuhanna, Sajesh Parathath, Etienne Morel, Manya Warrier, Janet K. Sawyer, Robert D. Gerard, Ryan E. Temel, J. Mark Brown, Margery Connelly, Chieko Mineo, Philip W. Shaul

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45 Scopus citations

Abstract

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. 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. 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. 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.

Original languageEnglish (US)
Pages (from-to)140-151
Number of pages12
JournalUnknown Journal
Volume112
Issue number1
DOIs
StatePublished - 2013

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ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Saddar, S., Carriere, V., Lee, W. R., Tanigaki, K., Yuhanna, I. S., Parathath, S., Morel, E., Warrier, M., Sawyer, J. K., Gerard, R. D., Temel, R. E., Brown, J. M., Connelly, M., Mineo, C., & Shaul, P. W. (2013). Scavenger receptor class B type I is a plasma membrane cholesterol sensor. Unknown Journal, 112(1), 140-151. https://doi.org/10.1161/CIRCRESAHA.112.280081