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Chemical modulation of chaperone-mediated autophagy by retinoic acid derivatives

A Corrigendum to this article was published on 18 October 2013

This article has been updated


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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Figure 1: Effect of knockdown of RARα on intracellular turnover of long-lived proteins.
Figure 2: Effect of knockdown of RARα on autophagic pathways.
Figure 3: Effect of ATRA on autophagy.
Figure 4: Design, synthesis and molecular docking of RARα-targeting compounds.
Figure 5: Effect of the chemical activators of CMA on RARα activity.
Figure 6: Characterization of the effect of the retinoid derivatives on CMA.
Figure 7: Effect of the retinoid derivatives in the cellular response against different stressors.

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  • 28 June 2013

    In the version of this article initially published, one of the three gray bars in Figure 6a was not defined, and the asterisks for these bars were misaligned. The errors have been corrected in the HTML and PDF versions of the article.


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We thank R. Valdor for technical assistance with the luciferase assay, R. Kiffin for assistance with the quantitative RT-PCR, F. Macian for help with fluorescence-activated cell sorting procedures, T. Evans and I. Torregroza for advice with the RARα luciferase assay, C.-L. Towse for advice on the simulated annealing and molecular dynamics simulations and S. Kaushik for critically reviewing this manuscript. This work was supported by grants from the US National Institutes of Health (NIH)–National Institute on Aging (AG021904 and AG031782 to A.M.C.); Albert Einstein College of Medicine start-up funds (to E.G.); NIH–National Heart, Lung, and Blood Institute (HL095929 to E.G.); NIH–National Institute on Alcohol Abuse and Alcoholism (AA020630 to B.C.D.); and by the Rainwaters Foundation, the Beatrice and Roy Backus Foundation and a Robert and Renee Belfer gift (to A.M.C.).

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Authors and Affiliations



J.A. performed the experiments, analyzed the data and contributed to writing the paper; T.P.G. performed the in silico docking and molecular dynamics simulations; M.M. contributed to the synthesis of chemical compounds; B.C.D. designed the chemical compounds, analyzed the chemical data and revised the manuscript; E.G. designed and directed the in silico docking and molecular dynamics simulations and contributed to the interpretation of the chemical data and to the writing and revising of the manuscript; and A.M.C. designed the biological experiments, directed the study and wrote the manuscript.

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Correspondence to Bhaskar C Das, Evripidis Gavathiotis or Ana Maria Cuervo.

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The authors declare no competing financial interests.

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Anguiano, J., Garner, T., Mahalingam, M. et al. Chemical modulation of chaperone-mediated autophagy by retinoic acid derivatives. Nat Chem Biol 9, 374–382 (2013).

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