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Aster Proteins Facilitate Nonvesicular Plasma Membrane to ER Cholesterol Transport in Mammalian Cells.

Citation
Sandhu, J., et al. “Aster Proteins Facilitate Nonvesicular Plasma Membrane To Er Cholesterol Transport In Mammalian Cells.”. Cell, pp. 514-529.e20.
Center UCSD-UCLA
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Author Jaspreet Sandhu, Shiqian Li, Louise Fairall, Simon G Pfisterer, Jennifer E Gurnett, Xu Xiao, Thomas A Weston, Dipti Vashi, Alessandra Ferrari, Jose L Orozco, Celine L Hartman, David Strugatsky, Stephen D Lee, Cuiwen He, Cynthia Hong, Haibo Jiang, Laurent A Bentolila, Alberto T Gatta, Tim P Levine, Annie Ferng, Richard Lee, David A Ford, Stephen G Young, Elina Ikonen, John W R Schwabe, Peter Tontonoz
Keywords HDL metabolism, LXR, SR-BI, SREBP, cholesterol, membrane contact sites, nonvesicular transport, steroidogenesis
Abstract

The mechanisms underlying sterol transport in mammalian cells are poorly understood. In particular, how cholesterol internalized from HDL is made available to the cell for storage or modification is unknown. Here, we describe three ER-resident proteins (Aster-A, -B, -C) that bind cholesterol and facilitate its removal from the plasma membrane. The crystal structure of the central domain of Aster-A broadly resembles the sterol-binding fold of mammalian StARD proteins, but sequence differences in the Aster pocket result in a distinct mode of ligand binding. The Aster N-terminal GRAM domain binds phosphatidylserine and mediates Aster recruitment to plasma membrane-ER contact sites in response to cholesterol accumulation in the plasma membrane. Mice lacking Aster-B are deficient in adrenal cholesterol ester storage and steroidogenesis because of an inability to transport cholesterol from SR-BI to the ER. These findings identify a nonvesicular pathway for plasma membrane to ER sterol trafficking in mammals.

Year of Publication
2018
Journal
Cell
Volume
175
Issue
2
Number of Pages
514-529.e20
Date Published
12/2018
ISSN Number
1097-4172
DOI
10.1016/j.cell.2018.08.033
Alternate Journal
Cell
PMID
30220461
PMCID
PMC6469685
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