1. Biochemistry and Chemical Biology
  2. Cell Biology
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Intracellular cholesterol trafficking is dependent upon NPC2 interaction with Lysobisphosphatidic Acid

Research Article
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Cite this article as: eLife 2019;8:e50832 doi: 10.7554/eLife.50832

Abstract

Unesterified cholesterol accumulation in the late endosomal/lysosomal (LE/LY) compartment is the cellular hallmark of Niemann-Pick C (NPC) disease, caused by defects in the genes encoding NPC1 or NPC2. We previously reported the dramatic stimulation of NPC2 cholesterol transport rates to and from model membranes by the LE/LY phospholipid lysobisphosphatidic acid (LBPA). It had been previously shown that enrichment of NPC1-deficient cells with LBPA results in cholesterol clearance. Here we demonstrate that LBPA enrichment in human NPC2-deficient cells, either directly or via its biosynthetic precursor phosphtidylglycerol (PG), is entirely ineffective, indicating an obligate functional interaction between NPC2 and LBPA in cholesterol trafficking. We further demonstrate that NPC2 interacts directly with LBPA and identify the NPC2 hydrophobic knob domain as the site of interaction. Together these studies reveal a heretofore unknown step of intracellular cholesterol trafficking which is critically dependent upon the interaction of LBPA with functional NPC2 protein.

Article and author information

Author details

  1. Leslie A McCauliff

    Department of Nutritional Sciences, Rutgers University, New Brunswick, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Annette Langan

    Department of Nutritional Sciences, Rutgers University, New Brunswick, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Ran Li

    Department of Nutritional Sciences, Rutgers University, New Brunswick, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Olga Ilnytska

    Department of Nutritional Sciences, Rutgers University, New Brunswick, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Debosreeta Bose

    Department of Nutritional Sciences, Rutgers University, New Brunswick, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Miriam Waghalter

    Department of Nutritional Sciences, Rutgers University, New Brunswick, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Kimberly Lai

    Department of Nutritional Sciences, Rutgers University, New Brunswick, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Peter C Kahn

    Department of Biochemistry and Microbiology, Rutgers University, New Brunswick, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Judith Storch

    Department of Nutritional Sciences, Rutgers University, New Brunswick, United States
    For correspondence
    storch@sebs.rutgers.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5482-1777

Funding

Ara Parseghian Medical Research Foundation

  • Olga Ilnytska
  • Judith Storch

American Heart Association (11PRE7330012)

  • Leslie A McCauliff

American Heart Association (18CDA34110230)

  • Olga Ilnytska

American Heart Association (14GRNT19990014)

  • Judith Storch

National Institutes of Health (GM 1125866)

  • Judith Storch

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Suzanne R Pfeffer, Stanford University School of Medicine, United States

Publication history

  1. Received: August 4, 2019
  2. Accepted: October 2, 2019
  3. Accepted Manuscript published: October 3, 2019 (version 1)
  4. Version of Record published: November 14, 2019 (version 2)

Copyright

© 2019, McCauliff et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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