Age-related Decline in Chaperone-mediated Autophagy*
Abstract
Intracellular protein degradation rates decrease with age in many tissues and organs. In cultured cells, chaperone-mediated autophagy, which is responsible for the selective degradation of cytosolic proteins in lysosomes, decreases with age. In this work we use lysosomes isolated from rat liver to analyze age-related changes in the levels and activities of the main components of chaperone-mediated autophagy. Lysosomes from “old” (22-month-old) rats show lower rates of chaperone-mediated autophagy, and both substrate binding to the lysosomal membrane and transport into lysosomes decline with age. A progressive age-related decrease in the levels of the lysosome-associated membrane protein type 2a that acts as a receptor for chaperone-mediated autophagy was responsible for decreased substrate binding in lysosomes from old rats as well as from late passage human fibroblasts. The cytosolic levels and activity of the 73-kDa heat-shock cognate protein required for substrate targeting to lysosomes were unchanged with age. The levels of lysosome-associated hsc73 were increased only in the oldest rats. This increase may be an attempt to compensate for reduced activity of the pathway with age.
Footnotes
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↵* This work was supported by National Institutes of Health Grants AG00829 (to A. M. C.) and AG06116 (to J. F. D.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵‡ To whom correspondence may be addressed: Dept. of Physiology, Tufts University School of Medicine,136 Harrison Ave, Boston, MA 02111. Tel.: 617-636-6707; Fax: 617-636-0445; E-mail: jdice@opal.tufts. edu or ana.cuervo{at}tufts.edu.
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Published, JBC Papers in Press, May 9, 2000, DOI 10.1074/jbc.M002102200
- Abbreviations:
- hsc73
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73-kDa heat-shock cognate protein
- MOPS
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3-(N-morpholino)propanesulfonic acid
- GAPDH
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glyceraldehyde-3-phosphate dehydrogenase
- ly-hsc73
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lysosomal hsc73
- lamp
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lysosome-associated membrane protein
- PDL
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population doubling level
- S-peptide
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residues 1–20 of RNase A
- PAGE
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polyacrylamide gel electrophoresis
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- Received March 14, 2000.
- Revision received May 4, 2000.
- The American Society for Biochemistry and Molecular Biology, Inc.
