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

Roberta Kiffin, Susmita Kaushik, Mei Zeng, Urmi Bandyopadhyay, Cong Zhang, Ashish C. Massey, Marta Martinez-Vicente, Ana Maria Cuervo

Research output: Contribution to journalArticle

132 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)782-791
Number of pages10
JournalJournal of cell science
Volume120
Issue number5
DOIs
StatePublished - Mar 1 2007

Keywords

  • Aging
  • Autophagy
  • Lipid microdomains
  • Lysosomal membrane proteins
  • Lysosomes
  • Proteases

ASJC Scopus subject areas

  • Cell Biology

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    Kiffin, R., Kaushik, S., Zeng, M., Bandyopadhyay, U., Zhang, C., Massey, A. C., Martinez-Vicente, M., & Cuervo, A. M. (2007). Altered dynamics of the lysosomal receptor for chaperone-mediated autophagy with age. Journal of cell science, 120(5), 782-791. https://doi.org/10.1242/jcs.001073