TY - JOUR
T1 - Chemical modulation of chaperone-mediated autophagy by retinoic acid derivatives
AU - Anguiano, Jaime
AU - Garner, Thomas P.
AU - Mahalingam, Murugesan
AU - Das, Bhaskar C.
AU - Gavathiotis, Evripidis
AU - Cuervo, Ana Maria
N1 - Funding Information:
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.).
PY - 2013/6
Y1 - 2013/6
N2 - 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.
AB - 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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U2 - 10.1038/nchembio.1230
DO - 10.1038/nchembio.1230
M3 - Article
C2 - 23584676
AN - SCOPUS:84879121285
SN - 1552-4450
VL - 9
SP - 374
EP - 382
JO - Nature Chemical Biology
JF - Nature Chemical Biology
IS - 6
ER -
