Activation of chaperone-mediated autophagy during oxidative stress

Roberta Kiffin, Christopher Christian, Erwin Knecht, Ana Maria Cuervo

Research output: Contribution to journalArticle

389 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4829-4840
Number of pages12
JournalMolecular biology of the cell
Volume15
Issue number11
DOIs
StatePublished - Nov 2004

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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