Chaperone-mediated autophagy and aging: a novel regulatory role of lipids revealed.
A wide pool of cytosolic proteins is selectively degraded in lysosomes by chaperonemediated autophagy (CMA). Binding of these proteins to a receptor at the lysosomal membrane is the limiting step in CMA. Levels of this receptor are tightly regulated through changes in its degradation, multimeric organization and dynamic distribution between the lysosomal membrane and lumen. We have now reported that subcompartmentalization of the receptor in discrete lipid microdomains at the lysosomal membrane regulates its engagement in each of these processes-degradation, multimerization and membrane retrieval. Changes in the lipid composition of the membrane thus affect the dynamics of the receptor and, consequently, CMA activity. As an example of CMA dysfunction resulting from perturbation of the lipid composition of the lysosomal membrane, we discuss here a second study in which we analyzed the changes in the dynamics of the receptor during aging. CMA activity decreases with age primarily due to a decrease in the levels of the CMA receptor at the lysosomal membrane. Now we have found that age-related alterations in the lipid composition of the discrete microdomains at the lysosomal membrane are behind the reduced lysosomal levels of the receptor and, consequently, the declined CMA activity that occurs during aging.
Kaushik
Susmita
S
Department of Anatomy and Structural Biology, Marion Bessin Liver ResearchCenter, Institute for Aging Research, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Kiffin
Roberta
R
Cuervo
Ana Maria
AM
D000375:Aging / Q000502:physiology*; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D008055:Lipids / Q000502:physiology*; D052119:Lysosomal-Associated Membrane Protein 2 / Q000235:genetics / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D021962:Membrane Microdomains / Q000378:metabolism; D008954:Models, Biological; D018832:Molecular Chaperones / Q000502:physiology*
D008055:Lipids; D052119:Lysosomal-Associated Membrane Protein 2; D018832:Molecular Chaperones