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Vol. 15, Issue 11, 4829-4840, November 2004
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* Department of Anatomy and Structural Biology, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY 10461;
Instituto de Investigaciones Citológicas, Fundación Valenciana de Investigaciones Biomédicas, Valencia 4010, Spain
Submitted June 11, 2004;
Revised August 3, 2004;
Accepted August 18, 2004
Monitoring Editor: Jennifer Lippincott-Schwartz
Oxidatively damaged proteins accumulate with age in almost all cell types and tissues. The activity of chaperone-mediated autophagy (CMA), a selective pathway for the degradation of cytosolic proteins in lysosomes, decreases with age. We have analyzed the possible participation of CMA in the removal of oxidized proteins in rat liver and cultured mouse fibroblasts. Added to the fact that CMA substrates, when oxidized, are more efficiently internalized into lysosomes, we have found a constitutive activation of CMA during oxidative stress. Oxidation-induced activation of CMA correlates with higher levels of several components of the lysosomal translocation complex, but in particular of the lumenal chaperone, required for substrate uptake, and of the lysosomal membrane protein (lamp) type 2a, previously identified as a receptor for this pathway. In contrast with the well characterized mechanism of CMA activation during nutritional stress, which does not require de novo synthesis of the receptor, oxidation-induced activation of CMA is attained through transcriptional up-regulation of lamp2a. We conclude that CMA is activated during oxidative stress and that the higher activity of this pathway under these conditions, along with the higher susceptibility of the oxidized proteins to be taken up by lysosomes, both contribute to the efficient removal of oxidized proteins.
Abbreviations used: CMA, chaperone-mediated autophagy; GAPDH, glyceraldehide-3-phosphate dehydrogenase; hsc70, heat shock cognate protein of 70 kDa; lamp, lysosomal associated membrane protein; MOPS, 3-(N-morpholino)propanesulfonic acid; RNase A, ribonuclease A.
The online version of this article contains supplementary material accessible through http://www.molbiolcell.org.
Corresponding author. E-mail address: amcuervo{at}aecom.yu.edu.
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