2. Academic Validation
  3. Aster Proteins Facilitate Nonvesicular Plasma Membrane to ER Cholesterol Transport in Mammalian Cells

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

  • Cell. 2018 Oct 4;175(2):514-529.e20. doi: 10.1016/j.cell.2018.08.033.
Jaspreet Sandhu 1,  Shiqian Li 2,  Louise Fairall 3,  Simon G Pfisterer 2,  Jennifer E Gurnett 3,  Xu Xiao 4,  Thomas A Weston 5,  Dipti Vashi 3,  Alessandra Ferrari 4,  Jose L Orozco 4,  Celine L Hartman 6,  David Strugatsky 7,  Stephen D Lee 4,  Cuiwen He 8,  Cynthia Hong 4,  Haibo Jiang 9,  Laurent A Bentolila 10,  Alberto T Gatta 11,  Tim P Levine 11,  Annie Ferng 12,  Richard Lee 12,  David A Ford 6,  Stephen G Young 13,  Elina Ikonen 2,  John W R Schwabe 3,  Peter Tontonoz 14
Affiliations

Affiliations

  • 1 Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 2 Department of Anatomy and Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki 00290, Finland; Minerva Foundation Institute for Medical Research, Helsinki 00290, Finland.
  • 3 Institute of Structural and Chemical Biology, Department of Molecular and Cell Biology, University of Leicester, Leicester LE1 7RH, UK.
  • 4 Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 5 Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 6 Edward A. Doisy Department of Biochemistry and Molecular Biology, and Center for Cardiovascular Research, Saint Louis University School of Medicine, St. Louis, MO 63104, USA.
  • 7 Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 8 Department of Medicine, Division of Cardiology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 9 Centre for Microscopy, Characterisation and Analysis, University of Western Australia, Perth 6009, Australia.
  • 10 California NanoSystems Institute, University of California, Los Angeles, CA 90095, USA.
  • 11 Department of Cell Biology, UCL Institute of Ophthalmology, London, UK.
  • 12 Ionis Pharmaceuticals, Carlsbad, CA 92008, USA.
  • 13 Department of Medicine, Division of Cardiology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 14 Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: ptontonoz@mednet.ucla.edu.
PMID: 30220461 DOI: 10.1016/j.cell.2018.08.033
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.

Keywords

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

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