Journal
JOURNAL OF CELL SCIENCE
Volume 120, Issue 5, Pages 782-791Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.001073
Keywords
aging; autophagy; lysosomes; lysosomal membrane proteins; proteases; lipid microdomains
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Funding
- NIA NIH HHS [AG-NS-0163, AG021904, T32AG023475, R01 AG021904, AG25355] Funding Source: Medline
- NIGMS NIH HHS [T32GM007491] Funding Source: Medline
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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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