Altered dynamics of the lysosomal receptor for chaperone-mediated autophagy with age

J Cell Sci. 2007 Mar 1;120(Pt 5):782-91. doi: 10.1242/jcs.001073. Epub 2007 Feb 6.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aging / physiology*
  • Animals
  • Autophagy*
  • Cells, Cultured
  • Electrophoresis, Polyacrylamide Gel
  • Gene Expression
  • Immunoblotting
  • Lysosomal Membrane Proteins / genetics
  • Lysosomal Membrane Proteins / metabolism*
  • Lysosomal-Associated Membrane Protein 2 / genetics
  • Lysosomal-Associated Membrane Protein 2 / metabolism
  • Lysosomes / metabolism*
  • Male
  • Membrane Microdomains / metabolism
  • Molecular Chaperones / metabolism*
  • Peptide Hydrolases / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Inbred F344
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • Lysosomal-Associated Membrane Protein 2
  • Lysosomal Membrane Proteins
  • Molecular Chaperones
  • RNA, Messenger
  • Peptide Hydrolases