Aster proteins facilitate nonvesicular plasma membrane to ER cholesterol transport in mammalian cells
journal contribution
posted on 2019-05-14, 10:36 authored by 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 TontonozThe 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.
Funding
We thank J. Kim, S. Munday, P. Rajbhandari, and T. Sallam for technical assistance and experimental guidance. Confocal microscopy was performed at the California NanoSystems Institute Advanced Light Microscopy/Spectroscopy Facility. We thank Diamond Light Source for beamtime (proposal MX14692) and the staff of beamlines I04-1, I03, and I24 for assistance with crystal testing and data collection. We dedicate this manuscript to the memory of Jaspal Singh Sandhu. His courageous battle with coronary artery disease has been a key inspiration to this work. J.S. was supported by NIH grants (GM08042 and T32HL69766) and a P. Whitcome Fellowship. J.O. was supported by an NIH grant (5T34GM008563). This research was also supported by grants from the NIH (HL066088, DK100627, S10RR019232, and GM115553), the Academy of Finland (307415, 312491, and 275964), the Sigrid Juselius Foundation, and the Helsinki Institute of Life Science Imaging Unit and Biomedicum Functional Genomics Unit. J.W.R.S. is a Wellcome Trust Senior Investigator (WT100237) and Royal Society Wolfson Research Merit Award Holder.
History
Citation
Cell, 2018, 175(2), pp. 514-529.e20Author affiliation
/Organisation/COLLEGE OF LIFE SCIENCES/Biological Sciences/Molecular & Cell BiologyVersion
- AM (Accepted Manuscript)
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CellPublisher
Elsevier (Cell Press)issn
0092-8674Acceptance date
2018-08-15Copyright date
2018Available date
2019-09-13Publisher DOI
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https://www.sciencedirect.com/science/article/pii/S0092867418310948Notes
The PDB Code for the crystallography data is PDB: 6GQF.;The file associated with this record is under embargo until 12 months after publication, in accordance with the publisher's self-archiving policy. The full text may be available through the publisher links provided above.Language
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