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. Epub 2018 Sep 13.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Animals
  • Biological Transport / physiology
  • CD36 Antigens / metabolism
  • CHO Cells
  • Carrier Proteins / metabolism
  • Cell Line
  • Cell Membrane / metabolism
  • Cell Membrane / physiology
  • Cholesterol / metabolism
  • Cholesterol, HDL / metabolism*
  • Cricetulus
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum / physiology
  • Humans
  • Membrane Proteins / metabolism
  • Membrane Proteins / physiology*
  • Membrane Proteins / ultrastructure*
  • Mice
  • Mice, Inbred C57BL
  • Mitochondrial Membranes / metabolism
  • Sequence Alignment
  • Sterols / metabolism


  • CD36 Antigens
  • Carrier Proteins
  • Cholesterol, HDL
  • GRAMD1A protein, human
  • Membrane Proteins
  • Sterols
  • Cholesterol