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

Area of Science:

• Lipid metabolism
• Cellular signaling
• Molecular biology

Background:

• High-density lipoprotein (HDL) receptor scavenger receptor class B, type I (SR-BI) initiates signaling essential for HDL's effects on endothelium.
• SR-BI's C-terminal transmembrane domain interacts with plasma membrane (PM) cholesterol, a process critical for signal initiation.

Purpose of the Study:

• To investigate the molecular basis of SR-BI's interaction with PM cholesterol.
• To determine the functional significance of this interaction in SR-BI signaling.
• To test if SR-BI acts as a PM cholesterol sensor.

Main Methods:

• Mutagenesis of SR-BI's C-terminal transmembrane domain (SR-BI-Q445A) to disrupt PM cholesterol interaction.
• Assays in COS-M6 cells to measure HDL binding, cholesterol uptake/efflux, and signaling.
• Studies in cultured enterocytes and endothelial cells, and in vivo angiogenesis models.

Main Results:

• SR-BI-Q445A mutation significantly reduced PM cholesterol interaction without affecting HDL binding or cholesterol transport.
• The mutation abolished HDL-induced signaling and signaling triggered by cholesterol efflux.
• PM cholesterol sensing by SR-BI is essential for apolipoprotein B trafficking, endothelial NO synthase activation, migration, and angiogenesis, but not liver reverse cholesterol transport.

Conclusions:

• SR-BI functions as a plasma membrane cholesterol sensor through its interaction with PM cholesterol.
• This sensing mechanism initiates intracellular signaling pathways governing critical functions in enterocytes and endothelial cells.