title: Chemical modulation of chaperone-mediated autophagy by retinoic acid derivatives.
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.
authors.affiliation: Department of Development and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Jaime
authors.initials: J
authors.lastname: Anguiano
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Garner
authors.forename: Murugesan
authors.initials: M
authors.lastname: Mahalingam
authors.forename: Bhaskar C
authors.initials: BC
authors.lastname: Das
authors.forename: Evripidis
authors.initials: E
authors.lastname: Gavathiotis
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Cuervo
mesh_terms: D000818:Animals; D001343:Autophagy; D001665:Binding Sites; D003600:Cytosol / Q000378:metabolism; D004247:DNA / Q000737:chemistry; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D018832:Molecular Chaperones / Q000737:chemistry*; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D041681:NIH 3T3 Cells; D010100:Oxygen / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin / Q000737:chemistry*
chemical_list: D018832:Molecular Chaperones; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin; D004247:DNA; D010100:Oxygen