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NPC1 regulates ER contacts with endocytic organelles to mediate cholesterol egress

Author

Listed:
  • D. Höglinger

    (University of Oxford
    Heidelberg University Biochemistry Center (BZH))

  • T. Burgoyne

    (UCL Institute of Ophthalmology
    Royal Brompton Hospital)

  • E. Sanchez-Heras

    (UCL Institute of Ophthalmology)

  • P. Hartwig

    (Heidelberg University Biochemistry Center (BZH))

  • A. Colaco

    (University of Oxford
    Danish Cancer Society Research Center)

  • J. Newton

    (Virginia Commonwealth University School of Medicine)

  • C. E. Futter

    (UCL Institute of Ophthalmology)

  • S. Spiegel

    (Virginia Commonwealth University School of Medicine)

  • F. M. Platt

    (University of Oxford)

  • E. R Eden

    (UCL Institute of Ophthalmology)

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.

Suggested Citation

  • D. Höglinger & T. Burgoyne & E. Sanchez-Heras & P. Hartwig & A. Colaco & J. Newton & C. E. Futter & S. Spiegel & F. M. Platt & E. R Eden, 2019. "NPC1 regulates ER contacts with endocytic organelles to mediate cholesterol egress," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12152-2
    DOI: 10.1038/s41467-019-12152-2
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    Cited by:

    1. Flavia Giamogante & Lucia Barazzuol & Francesca Maiorca & Elena Poggio & Alessandra Esposito & Anna Masato & Gennaro Napolitano & Alessio Vagnoni & Tito Calì & Marisa Brini, 2024. "A SPLICS reporter reveals $${{{{{\boldsymbol{\alpha }}}}}}$$ α -synuclein regulation of lysosome-mitochondria contacts which affects TFEB nuclear translocation," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    2. Tomoki Naito & Haoning Yang & Dylan Hong Zheng Koh & Divyanshu Mahajan & Lei Lu & Yasunori Saheki, 2023. "Regulation of cellular cholesterol distribution via non-vesicular lipid transport at ER-Golgi contact sites," Nature Communications, Nature, vol. 14(1), pages 1-25, December.
    3. Yuzhe Weng & Dawn Shepherd & Yi Liu & Nitya Krishnan & Brian D. Robertson & Nick Platt & Gerald Larrouy-Maumus & Frances M. Platt, 2022. "Inhibition of the Niemann-Pick C1 protein is a conserved feature of multiple strains of pathogenic mycobacteria," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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