Chemical modulation of chaperone-mediated autophagy by retinoic acid derivatives

Jaime Anguiano, Thomas P. Garner, Murugesan Mahalingam, Bhaskar C. Das, Evripidis Gavathiotis, Ana Maria Cuervo

Research output: Contribution to journalArticle

87 Scopus citations

Abstract

Chaperone-mediated autophagy (CMA) contributes to cellular quality control and the cellular response to stress through the selective degradation of cytosolic proteins in lysosomes. A decrease in CMA activity occurs in aging and in age-related disorders (for example, neurodegenerative diseases and diabetes). Although prevention of this age-dependent decline through genetic manipulation in mice has proven beneficial, chemical modulation of CMA is not currently possible, owing in part to the lack of information on the signaling mechanisms that modulate this pathway. In this work, we report that signaling through retinoic acid receptor α (RARα) inhibits CMA and apply structure-based chemical design to develop synthetic derivatives of all-trans-retinoic acid to specifically neutralize this inhibitory effect. We demonstrate that chemical enhancement of CMA protects cells from oxidative stress and from proteotoxicity, supporting a potential therapeutic opportunity when reduced CMA contributes to cellular dysfunction and disease.

Original languageEnglish (US)
Pages (from-to)374-382
Number of pages9
JournalNature Chemical Biology
Volume9
Issue number6
DOIs
StatePublished - Jun 1 2013

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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