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

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

doi:10.1016/j.cell.2018.08.033

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

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

Research output: Contribution to journal › Article › peer-review

219 Scopus citations

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. A nonvesicular pathway for plasma membrane to ER sterol trafficking in mammals is mediated by sterol-binding ER-resident Aster proteins.

Original language	English
Pages (from-to)	514-529.e20
Journal	Cell
Volume	175
Issue number	2
DOIs	https://doi.org/10.1016/j.cell.2018.08.033
State	Published - Oct 4 2018

Bibliographical note

Publisher Copyright:
© 2018 Elsevier Inc.

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.

Funders	Funder number
National Institutes of Health (NIH)
Helsinki Institute of Life Science Imaging Unit
Sigrid Juséliuksen Säätiö
National Institute of Diabetes and Digestive and Kidney Diseases	R01DK100627
National Heart, Lung, and Blood Institute (NHLBI)	R01HL136618, T32HL069766, R01HL066088
National Institute of General Medical Sciences DP2GM119177 Sophie Dumont National Institute of General Medical Sciences	T34GM008563, T32GM008042, R01GM115553
Biotechnology and Biological Sciences Research Council	BB/P003818/1, BB/M011801/1
Academy of Finland	312491, 307415
Seventh Framework Programme	275964
Wellcome Trust	WT100237
National Center for Research Resources	S10RR019232

Keywords

HDL metabolism
LXR
SR-BI
SREBP
cholesterol
membrane contact sites
nonvesicular transport
steroidogenesis

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2018.08.033

Cite this

Sandhu, J., Li, S., Fairall, L., Pfisterer, S. G., Gurnett, J. E., Xiao, X., Weston, T. A., Vashi, D., Ferrari, A., Orozco, J. L., Hartman, C. L., Strugatsky, D., Lee, S. D., He, C., Hong, C., Jiang, H., Bentolila, L. A., Gatta, A. T., Levine, T. P., ... Tontonoz, P. (2018). Aster Proteins Facilitate Nonvesicular Plasma Membrane to ER Cholesterol Transport in Mammalian Cells. Cell, 175(2), 514-529.e20. https://doi.org/10.1016/j.cell.2018.08.033

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title = "Aster Proteins Facilitate Nonvesicular Plasma Membrane to ER Cholesterol Transport in Mammalian Cells",

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. A nonvesicular pathway for plasma membrane to ER sterol trafficking in mammals is mediated by sterol-binding ER-resident Aster proteins.",

keywords = "HDL metabolism, LXR, SR-BI, SREBP, cholesterol, membrane contact sites, nonvesicular transport, steroidogenesis",

author = "Jaspreet Sandhu and Shiqian Li and Louise Fairall and Pfisterer, \{Simon G.\} and Gurnett, \{Jennifer E.\} and Xu Xiao and Weston, \{Thomas A.\} and Dipti Vashi and Alessandra Ferrari and Orozco, \{Jose L.\} and Hartman, \{Celine L.\} and David Strugatsky and Lee, \{Stephen D.\} and Cuiwen He and Cynthia Hong and Haibo Jiang and Bentolila, \{Laurent A.\} and Gatta, \{Alberto T.\} and Levine, \{Tim P.\} and Annie Ferng and Richard Lee and Ford, \{David A.\} and Young, \{Stephen G.\} and Elina Ikonen and Schwabe, \{John W.R.\} and Peter Tontonoz",

note = "Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",

year = "2018",

month = oct,

day = "4",

doi = "10.1016/j.cell.2018.08.033",

language = "English",

volume = "175",

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Sandhu, J, Li, S, Fairall, L, Pfisterer, SG, Gurnett, JE, Xiao, X, Weston, TA, Vashi, D, Ferrari, A, Orozco, JL, Hartman, CL, Strugatsky, D, Lee, SD, He, C, Hong, C, Jiang, H, Bentolila, LA, Gatta, AT, Levine, TP, Ferng, A, Lee, R, Ford, DA, Young, SG, Ikonen, E, Schwabe, JWR & Tontonoz, P 2018, 'Aster Proteins Facilitate Nonvesicular Plasma Membrane to ER Cholesterol Transport in Mammalian Cells', Cell, vol. 175, no. 2, pp. 514-529.e20. https://doi.org/10.1016/j.cell.2018.08.033

TY - JOUR

T1 - Aster Proteins Facilitate Nonvesicular Plasma Membrane to ER Cholesterol Transport in Mammalian Cells

AU - Sandhu, Jaspreet

AU - Li, Shiqian

AU - Fairall, Louise

AU - Pfisterer, Simon G.

AU - Gurnett, Jennifer E.

AU - Xiao, Xu

AU - Weston, Thomas A.

AU - Vashi, Dipti

AU - Ferrari, Alessandra

AU - Orozco, Jose L.

AU - Hartman, Celine L.

AU - Strugatsky, David

AU - Lee, Stephen D.

AU - He, Cuiwen

AU - Hong, Cynthia

AU - Jiang, Haibo

AU - Bentolila, Laurent A.

AU - Gatta, Alberto T.

AU - Levine, Tim P.

AU - Ferng, Annie

AU - Lee, Richard

AU - Ford, David A.

AU - Young, Stephen G.

AU - Ikonen, Elina

AU - Schwabe, John W.R.

AU - Tontonoz, Peter

PY - 2018/10/4

Y1 - 2018/10/4

N2 - 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. A nonvesicular pathway for plasma membrane to ER sterol trafficking in mammals is mediated by sterol-binding ER-resident Aster proteins.

AB - 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. A nonvesicular pathway for plasma membrane to ER sterol trafficking in mammals is mediated by sterol-binding ER-resident Aster proteins.

KW - HDL metabolism

KW - LXR

KW - SR-BI

KW - SREBP

KW - cholesterol

KW - membrane contact sites

KW - nonvesicular transport

KW - steroidogenesis

UR - https://www.scopus.com/pages/publications/85054250172

UR - https://www.scopus.com/pages/publications/85054250172#tab=citedBy

U2 - 10.1016/j.cell.2018.08.033

DO - 10.1016/j.cell.2018.08.033

M3 - Article

C2 - 30220461

AN - SCOPUS:85054250172

SN - 0092-8674

VL - 175

SP - 514-529.e20

JO - Cell

JF - Cell

IS - 2

ER -

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

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

Access to Document

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