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Aster Proteins Regulate the Accessible Cholesterol Pool in the Plasma Membrane.

Authors :
Ferrari, Alessandra
Cuiwen He
Kennelly, John Paul
Sandhu, Jaspreet
Xu Xiao
Xun Chi
Haibo Jiang
Young, Stephen G.
Tontonoz, Peter
Source :
Molecular & Cellular Biology; Oct2020, Vol. 40 Issue 19, p1-12, 12p
Publication Year :
2020

Abstract

Recent studies have demonstrated the existence of a discrete pool of cholesterol in the plasma membranes (PM) of mammalian cells--referred to as the accessible cholesterol pool--that can be detected by the binding of modified versions of bacterial cytolysins (e.g., anthrolysin O). When the amount of accessible cholesterol in the PM exceeds a threshold level, the excess cholesterol moves to the endoplasmic reticulum (ER), where it regulates the SREBP2 pathway and undergoes esterification. We reported previously that the Aster/Gramd1 family of sterol transporters mediates nonvesicular movement of cholesterol from the PM to the ER in multiple mammalian cell types. Here, we investigated the PM pool of accessible cholesterol in cholesterol-loaded fibroblasts with a knockdown of Aster-A and in mouse macrophages from Aster-B and Aster-A/B-deficient mice. Nanoscale secondary ion mass spectrometry (NanoSIMS) analyses revealed expansion of the accessible cholesterol pool in cells lacking Aster expression. The increased accessible cholesterol pool in the PM was accompanied by reduced cholesterol movement to the ER, evidenced by increased expression of SREBP2-regulated genes. Cosedimentation experiments with liposomes revealed that the Aster-B GRAM domain binds to membranes in a cholesterol concentration-dependent manner and that the binding is facilitated by the presence of phosphatidylserine. These studies revealed that the Aster-mediated nonvesicular cholesterol transport pathway controls levels of accessible cholesterol in the PM, as well as the activity of the SREBP pathway. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
02707306
Volume :
40
Issue :
19
Database :
Complementary Index
Journal :
Molecular & Cellular Biology
Publication Type :
Academic Journal
Accession number :
146003313
Full Text :
https://doi.org/10.1128/MCB.00255-20