NPC1 regulates ER contacts with endocytic organelles to mediate cholesterol egress

  • Nat Commun. 2019 Sep 19;10(1):4276. doi: 10.1038/s41467-019-12152-2.
D Höglinger  1  2 ,  T Burgoyne  3  4 ,  E Sanchez-Heras  3 ,  P Hartwig  2 ,  A Colaco  1  5 ,  J Newton  6 ,  C E Futter  3 ,  S Spiegel  6 ,  F M Platt  1 ,  E R Eden  7
Affiliations
  • 1. Department of Pharmacology, University of Oxford, Oxford, UK.
  • 2. Heidelberg University Biochemistry Center (BZH), Heidelberg, Germany.
  • 3. UCL Institute of Ophthalmology, London, UK.
  • 4. Paediatric Respiratory Department, Royal Brompton Hospital, London, UK.
  • 5. Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, Copenhagen, Denmark.
  • 6. Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298, USA.
  • 7. UCL Institute of Ophthalmology, London, UK. [email protected].
PMID: 31537798 DOI: 10.1038/s41467-019-12152-2
Abstract

Transport of dietary Cholesterol from endocytic organelles to the endoplasmic reticulum (ER) is essential for Cholesterol homoeostasis, but the mechanism and regulation of this transport remains poorly defined. Membrane contact sites (MCS), microdomains of close membrane apposition, are gaining attention as important platforms for non-vesicular, inter-organellar communication. Here we investigate the impact of ER-endocytic organelle MCS on Cholesterol transport. We report a role for Niemann-Pick type C protein 1 (NPC1) in tethering ER-endocytic organelle MCS where it interacts with the ER-localised sterol transport protein Gramd1b to regulate Cholesterol egress. We show that artificially tethering MCS rescues the Cholesterol accumulation that characterises NPC1-deficient cells, consistent with direct lysosome to ER Cholesterol transport across MCS. Finally, we identify an expanded population of lysosome-mitochondria MCS in cells depleted of NPC1 or Gramd1b that is dependent on the late endosomal sterol-binding protein STARD3, likely underlying the mitochondrial Cholesterol accumulation in NPC1-deficient cells.