c-Abl Inhibition Activates TFEB and Promotes Cellular Clearance in a Lysosomal Disorder

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dc.contributor.authorContreras, Pablo
dc.contributor.authorTapia, Pablo
dc.contributor.authorGonzález-Hodar, Lila
dc.contributor.authorPeluso, Ivana
dc.contributor.authorSoldati, Chiara
dc.contributor.authorNapoiotano, Gennaro
dc.contributor.authorMatarese, María
dc.contributor.authorLas Heras, Macarena
dc.contributor.authorValls, Cristian
dc.contributor.authorMartínez, Alexis
dc.contributor.authorBalboa, Elisa
dc.contributor.authorCastro, Juan
dc.contributor.authorNancy, Leal
dc.contributor.authorPlatt, Frances
dc.contributor.authorSobota, Andrzej
dc.contributor.authorWinter, Dominic
dc.contributor.authorKlein, Andrés
dc.contributor.authorMedina, Diego
dc.contributor.authorBallabio, Andrea
dc.contributor.authorAlvarez, Alejandra
dc.contributor.authorZanlungo, Silvana
dc.date.accessioned2020-12-18T16:37:34Z
dc.date.available2020-12-18T16:37:34Z
dc.date.issued2020
dc.descriptionCentro de Genética y Genómicaes
dc.description.abstractThe transcription factor EB (TFEB) has emerged as a master regulator of lysosomal biogenesis, exocytosis, and autophagy, promoting the clearance of substrates stored in cells. c-Abl is a tyrosine kinase that participates in cellular signaling in physiological and pathophysiological conditions. In this study, we explored the connection between c-Abl and TFEB. Here, we show that under pharmacological and genetic c-Abl inhibition, TFEB translocates into the nucleus promoting the expression of its target genes independently of its well-known regulator, mammalian target of rapamycin complex 1. Active c-Abl induces TFEB phosphorylation on tyrosine and the inhibition of this kinase promotes lysosomal biogenesis, autophagy, and exocytosis. c-Abl inhibition in Niemann-Pick type C (NPC) models, a neurodegenerative disease characterized by cholesterol accumulation in lysosomes, promotes a cholesterol-lowering effect in a TFEB-dependent manner. Thus, c-Abl is a TFEB regulator that mediates its tyrosine phosphorylation, and the inhibition of c-Abl activates TFEB promoting cholesterol clearance in NPC models.es
dc.identifier.citationPablo S. Contreras, Pablo J. Tapia, Lila González-Hódar, Ivana Peluso, Chiara Soldati, Gennaro Napolitano, Maria Matarese, Macarena Las Heras, Cristian Valls, Alexis Martinez, Elisa Balboa, Juan Castro, Nancy Leal, Frances M. Platt, Andrzej Sobota, Dominic Winter, Andrés D. Klein, Diego L. Medina, Andrea Ballabio, Alejandra R. Alvarez, Silvana Zanlungo, c-Abl Inhibition Activates TFEB and Promotes Cellular Clearance in a Lysosomal Disorder (2020) iScience 23(11)es
dc.identifier.urihttps://doi.org/10.1016/j.isci.2020.101691es
dc.identifier.urihttp://hdl.handle.net/11447/3639
dc.language.isoenes
dc.publisherCell Presses
dc.subjectCiencias biológicases
dc.subjectBiología moleculares
dc.subjectBiología celurares
dc.titlec-Abl Inhibition Activates TFEB and Promotes Cellular Clearance in a Lysosomal Disorderes
dc.typeArticlees

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