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Lysosomal membrane glycoproteins bind cholesterol and contribute to lysosomal cholesterol export
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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“Levels of LAMP1/2, which are involved in NPC2 to NPC1 cholesterol export pathway from lysosome were decreased in APOE4 astrocytes and microglia (Figures S6E and S6F) in which LAMP1 deficiency causes defective lysosome-ER cholesterol transport and lysosomal cholesterol accumulation (Li and Pfeffer, 2016).”
From Cholesterol and matrisome pathways dysregulated in astrocytes and microglia (2022) · cites this paper as Li and Pfeffer, 2016
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“Levels of LAMP1/2, which are involved in NPC2 to NPC1 cholesterol export pathway from lysosome were decreased in APOE4 astrocytes and microglia (Figures S6E and S6F) in which LAMP1 deficiency causes defective lysosome-ER cholesterol transport and lysosomal cholesterol accumulation (Li and Pfeffer, 2016).”
From Cholesterol and matrisome pathways dysregulated in astrocytes and microglia (2022) · cites this paper as Li and Pfeffer, 2016
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Cited by
Sorted by citations
Mechanisms and regulation of cholesterol homeostasis
Luo, J., Yang, H., & Song, B.-L. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-019-0190-7 · Cited by 1,980
Cholesterol and matrisome pathways dysregulated in astrocytes and microglia
TCW, J., Qian, L., Pipalia, N. H., Chao, M. J., Liang, S. A., Shi, Y., Jain, B. R., Bertelsen, S. E., Kapoor, M., Marcora, E., et al. (2022) · Cell · doi:10.1016/j.cell.2022.05.017 · Cited by 411
Notomi, S., Ishihara, K., Efstathiou, N. E., Lee, J.-J., Hisatomi, T., Tachibana, T., Konstantinou, E. K., Ueta, T., Murakami, Y., Maidana, D. E., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1906643116 · Cited by 92
Metadata
- Authors
- Li, J., & Pfeffer, S. R.
- Affiliations
- Department of Biochemistry, Stanford University School of Medicine, Stanford, United States
- ORCID
- Pfeffer, Suzanne R
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2016-09-24
- Volume
- 5
- ISSN
- 2050-084X
- PMC
- PMC5068966
- Cited by
- 111
- References
- 1
- Language
- en
- Licence
- Funders
- Ara Parseghian Medical Research Foundation
- National Institute of Diabetes and Digestive and Kidney Diseases (DK37332)
- National Institutes of Health (P30 CA124435)
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