Altered dynamics of the lysosomal receptor for chaperone-mediated autophagy with age.
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.
Kiffin
Roberta
R
Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Kaushik
Susmita
S
Zeng
Mei
M
Bandyopadhyay
Urmi
U
Zhang
Cong
C
Massey
Ashish C
AC
Martinez-Vicente
Marta
M
Cuervo
Ana Maria
AM
D000375:Aging / Q000502:physiology*; D000818:Animals; D001343:Autophagy; D002478:Cells, Cultured; D004591:Electrophoresis, Polyacrylamide Gel; D015870:Gene Expression; D015151:Immunoblotting; D052119:Lysosomal-Associated Membrane Protein 2 / Q000235:genetics / Q000378:metabolism; D051907:Lysosomal Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism*; D008297:Male; D021962:Membrane Microdomains / Q000378:metabolism; D018832:Molecular Chaperones / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction
D052119:Lysosomal-Associated Membrane Protein 2; D051907:Lysosomal Membrane Proteins; D018832:Molecular Chaperones; D012333:RNA, Messenger; D010447:Peptide Hydrolases