[HTML][HTML] Crucial step in cholesterol homeostasis: sterols promote binding of SCAP to INSIG-1, a membrane protein that facilitates retention of SREBPs in ER
Cell, 2002•cell.com
Using coimmunoprecipitation and tandem mass spectrometry, we identify INSIG-1 as an ER
protein that binds the sterol-sensing domain of SREBP cleavage-activating protein (SCAP)
and facilitates retention of the SCAP/SREBP complex in the ER. In sterol-depleted cells,
SCAP escorts SREBPs from ER to Golgi for proteolytic processing, thereby allowing
SREBPs to stimulate cholesterol synthesis. Sterols induce binding of SCAP to INSIG-1, as
determined by blue native-PAGE, and this is correlated with the inhibition of SCAP exit from …
protein that binds the sterol-sensing domain of SREBP cleavage-activating protein (SCAP)
and facilitates retention of the SCAP/SREBP complex in the ER. In sterol-depleted cells,
SCAP escorts SREBPs from ER to Golgi for proteolytic processing, thereby allowing
SREBPs to stimulate cholesterol synthesis. Sterols induce binding of SCAP to INSIG-1, as
determined by blue native-PAGE, and this is correlated with the inhibition of SCAP exit from …
Abstract
Using coimmunoprecipitation and tandem mass spectrometry, we identify INSIG-1 as an ER protein that binds the sterol-sensing domain of SREBP cleavage-activating protein (SCAP) and facilitates retention of the SCAP/SREBP complex in the ER. In sterol-depleted cells, SCAP escorts SREBPs from ER to Golgi for proteolytic processing, thereby allowing SREBPs to stimulate cholesterol synthesis. Sterols induce binding of SCAP to INSIG-1, as determined by blue native-PAGE, and this is correlated with the inhibition of SCAP exit from the ER. Overexpression of INSIG-1 increases the sensitivity of cells to sterol-mediated inhibition of SREBP processing. Mutant SCAP(Y298C) fails to bind INSIG-1 and is resistant to sterol-mediated inhibition of ER exit. By facilitating sterol-dependent ER retention of SCAP, INSIG-1 plays a central role in cholesterol homeostasis.
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