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Vol. 19, Issue 5, 2179-2192, May 2008

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Constitutive Activation of Chaperone-mediated Autophagy in Cells with Impaired Macroautophagy

Susmita Kaushik^*, Ashish C. Massey^*, Noboru Mizushima, and Ana Maria Cuervo^*

*Departments of Anatomy and Structural Biology and Developmental and Molecular Biology, Marion Bessin Liver Research Center and Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY 10461; and Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Tokyo, 113-8519, Japan

Submitted November 19, 2007; Revised February 20, 2008; Accepted March 3, 2008
Monitoring Editor: Suresh Subramani

Three different types of autophagy—macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA)—contribute to degradation of intracellular components in lysosomes in mammalian cells. Although some level of basal macroautophagy and CMA activities has been described in different cell types and tissues, these two pathways are maximally activated under stress conditions. Activation of these two pathways is often sequential, suggesting the existence of some level of cross-talk between both stress-related autophagic pathways. In this work, we analyze the consequences of blockage of macroautophagy on CMA activity. Using mouse embryonic fibroblasts deficient in Atg5, an autophagy-related protein required for autophagosome formation, we have found that blockage of macroautophagy leads to up-regulation of CMA, even under basal conditions. Interestingly, different mechanisms contribute to the observed changes in CMA-related proteins and the consequent activation of CMA during basal and stress conditions in these macroautophagy-deficient cells. This work supports a direct cross-talk between these two forms of autophagy, and it identifies changes in the lysosomal compartment that underlie the basis for the communication between both autophagic pathways.

Address correspondence to: Ana Maria Cuervo (amcuervo{at}aecom.yu.edu)

Abbreviations used: Atg, autophagy-related protein; CMA, chaperone-mediated autophagy; hsc70, heat-shock cognate protein of 70 kDa; LAMP, lysosome-associated membrane protein; MOPS, 3-(N-morpholino)propanesulfonic acid.