Lysosomal membrane glycoproteins bind cholesterol and contribute to lysosomal cholesterol export

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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 human 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 human LAMP2 to facilitate cholesterol export from lysosomes relies on its ability to bind cholesterol directly.

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Jian Li

Department of Biochemistry, Stanford University School of Medicine, Stanford, United States

Competing interests
No competing interests declared.
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.

"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.

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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.