Lysosomal membrane glycoproteins bind cholesterol and contribute to lysosomal cholesterol export

  1. Jian Li
  2. Suzanne R Pfeffer  Is a corresponding author
  1. Stanford University School of Medicine, United States

Abstract

LAMP1 and LAMP2 proteins are highly abundant, ubiquitous, mammalian proteins that line the lysosome limiting membrane, and protect it from lysosomal hydrolase action. LAMP2 deficiency causes Danon's disease, an X-linked hypertrophic cardiomyopathy. LAMP2 is needed for chaperone-mediated autophagy, and its expression improves tissue function in models of aging. We show here that LAMP1 and LAMP2 bind cholesterol in a manner that buries the cholesterol 3β-hydroxyl group; they also bind tightly to NPC1 and NPC2 proteins that export cholesterol from lysosomes. Quantitation of cellular LAMP2 and NPC1 protein levels suggest that LAMP proteins represent a significant cholesterol binding site at the lysosome limiting membrane, and may signal cholesterol availability. Functional rescue experiments show that the ability of LAMP2 to facilitate cholesterol export from lysosomes relies on its ability to bind cholesterol directly.

Article and author information

Author details

  1. Jian Li

    Department of Biochemistry, Stanford University School of Medicine, Stanford, United States
    Competing interests
    No competing interests declared.
  2. Suzanne R Pfeffer

    Department of Biochemistry, Stanford University School of Medicine, Stanford, United States
    For correspondence
    pfeffer@stanford.edu
    Competing interests
    Suzanne R Pfeffer, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6462-984X

Funding

Ara Parseghian Medical Research Foundation

  • Jian Li
  • Suzanne R Pfeffer

National Institute of Diabetes and Digestive and Kidney Diseases (DK37332)

  • Suzanne R Pfeffer

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

Reviewing Editor

  1. Chris G Burd, Yale University, United States

Publication history

  1. Received: September 19, 2016
  2. Accepted: September 23, 2016
  3. Accepted Manuscript published: September 24, 2016 (version 1)
  4. Accepted Manuscript updated: October 6, 2016 (version 2)
  5. Version of Record published: October 18, 2016 (version 3)

Copyright

© 2016, Li & Pfeffer

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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  1. Jian Li
  2. Suzanne R Pfeffer
(2016)
Lysosomal membrane glycoproteins bind cholesterol and contribute to lysosomal cholesterol export
eLife 5:e21635.
https://doi.org/10.7554/eLife.21635

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