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First published online 6 February 2007
doi: 10.1242/jcs.001073

Journal of Cell Science 120, 782-791 (2007)
Published by The Company of Biologists 2007
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Research Article

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 and Ana Maria Cuervo{ddagger}

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

{ddagger} Author for correspondence (e-mail: amcuervo{at}aecom.yu.edu)

Accepted 4 January 2007

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.

Key words: Aging, Autophagy, Lysosomes, Lysosomal membrane proteins, Proteases, Lipid microdomains




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