Altered dynamics of the lysosomal receptor for chaperone-mediated autophagy with age
Abstract
Rates of autophagy, the mechanism responsible for lysosomal clearance of cellular components, decrease with age. We have previously described an age-related decline in chaperone-mediated autophagy (CMA), a selective form of autophagy, by which particular cytosolic proteins are delivered to lysosomes after binding to the lysosome-associated membrane protein type 2A (LAMP-2A), a receptor for this pathway. Rates of CMA decrease with age because of a decrease in the levels of LAMP-2A. In this work we have investigated the reasons for the reduced levels of LAMP-2A with age. While transcriptional rates of LAMP-2A remain unchanged with age, the dynamics and stability of the receptor in the lysosomal compartment are altered. The mobilization of the lysosomal lumenal LAMP-2A to the membrane when CMA is activated is altered in lysosomes from old animals, leading to the presence of an unstable pool of lumenal LAMP-2A. By contrast, the regulated cleavage of LAMP-2A at the lysosomal membrane is reduced owing to altered association of the receptor and the protease responsible for its cleavage to particular membrane microdomain regions. We conclude that age-related changes at the lysosomal membrane are responsible for the altered turnover of the CMA receptor in old organisms and the consequent decline in this pathway.
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Changes with age in the lipid composition of the lysosomal membrane are likely behind the instability of LAMP-2A in old organisms.
“Changes with age in the lipid composition of the lysosomal membrane are likely behind the instability of LAMP-2A in old organisms (Kiffin et al., 2007).”
From Protein Homeostasis and Aging: the importance of exquisite quality control (2011) · cites this paper as Kiffin et al., 2007
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Self-citation
- Authors
- Kiffin, R., Kaushik, S., Zeng, M., Bandyopadhyay, U., Zhang, C., Massey, A. C., Martinez-Vicente, M., & Cuervo, A. M.
- Affiliations
- Albert Einstein College of Medicine (US)
- Department of Anatomy and Structural Biology, Department of Developmental and Molecular Biology and Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA
- Venue
- Journal of Cell Science
- Publisher
- The Company of Biologists
- Published
- 2007-03-01
- Volume
- 120
- Issue
- 5
- Pages
- 782-791
- ISSN
- 0021-9533 (ISSN-L)
- 1477-9137
- OpenAlex
- W1990012982
- Cited by
- 213
- References
- 36
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 15 · 2023: 13 · 2022: 12 · 2021: 13 · 2020: 9 · 2019: 12 · 2018: 16 · 2017: 10 · 2016: 11 · 2015: 12 · 2014: 7 · 2013: 10 · 2012: 8
- FWCI
- 9.21
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Cell Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (R01AG021904, AG-25355, AG-NS-0163, AG-021904, R21AG025355, T32AG023475)
- National Institute of General Medical Sciences (T32GM007491)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- chaperone-mediated autophagy, LAMP2A, aging, lysosomal membrane, receptor turnover, proteolytic cleavage, lipid rafts, lysosomal clearance
- MeSH terms
- Aging, Animals, Autophagy, Cells, Cultured, Electrophoresis, Polyacrylamide Gel, Lysosomes, Male, Peptide Hydrolases, Rats, Inbred F344, RNA, Messenger, Immunoblotting, Gene Expression, Molecular Chaperones, Reverse Transcriptase Polymerase Chain Reaction, Membrane Microdomains, Rats, Lysosomal Membrane Proteins, Lysosomal-Associated Membrane Protein 2
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