Chemical Modulation of Chaperone-mediated Autophagy by Retinoic Acid Derivatives

Overview

Journal Nat Chem Biol

Specialties Biochemistry
Biology
Chemistry

Date 2013 Apr 16

PMID 23584676

Citations 124

Authors

Jaime Anguiano

Thomas P Garner

Murugesan Mahalingam

Bhaskar C Das

Evripidis Gavathiotis

Ana Maria Cuervo

Affiliations

Soon will be listed here.

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.

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