Annexin A1 Tethers Membrane Contact Sites that Mediate ER to Endosome Cholesterol Transport

Dev Cell. 2016 Jun 6;37(5):473-83. doi: 10.1016/j.devcel.2016.05.005.


Membrane contact sites between the ER and multivesicular endosomes/bodies (MVBs) play important roles in endosome positioning and fission and in neurite outgrowth. ER-MVB contacts additionally function in epidermal growth factor receptor (EGFR) tyrosine kinase downregulation by providing sites where the ER-localized phosphatase, PTP1B, interacts with endocytosed EGFR before the receptor is sorted onto intraluminal vesicles (ILVs). Here we show that these contacts are tethered by annexin A1 and its Ca(2+)-dependent ligand, S100A11, and form a subpopulation of differentially regulated contact sites between the ER and endocytic organelles. Annexin A1-regulated contacts function in the transfer of ER-derived cholesterol to the MVB when low-density lipoprotein-cholesterol in endosomes is low. This sterol traffic depends on interaction between ER-localized VAP and endosomal oxysterol-binding protein ORP1L, and is required for the formation of ILVs within the MVB and thus for the spatial regulation of EGFR signaling.

MeSH terms

  • Annexin A1 / metabolism*
  • Biological Transport / drug effects
  • Cholesterol / metabolism*
  • Endocytosis / drug effects
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / metabolism*
  • Endoplasmic Reticulum / ultrastructure
  • Endosomes / drug effects
  • Endosomes / metabolism*
  • Endosomes / ultrastructure
  • Epidermal Growth Factor / pharmacology
  • ErbB Receptors / metabolism
  • HeLa Cells
  • Humans
  • Lipoproteins, LDL / pharmacology
  • Multivesicular Bodies / drug effects
  • Multivesicular Bodies / metabolism
  • Multivesicular Bodies / ultrastructure
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism
  • Receptors, Steroid / metabolism
  • Transport Vesicles / drug effects
  • Transport Vesicles / metabolism
  • Vesicular Transport Proteins / metabolism


  • Annexin A1
  • Lipoproteins, LDL
  • Receptors, Steroid
  • VAPA protein, human
  • VAPB protein, human
  • Vesicular Transport Proteins
  • oxysterol binding protein
  • Epidermal Growth Factor
  • Cholesterol
  • ErbB Receptors
  • PTPN1 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1