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

The 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 th...

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Published in:iScience 2020-11, Vol.23 (11), p.101691-101691, Article 101691
Main Authors: Contreras, Pablo S., Tapia, Pablo J., González-Hódar, Lila, Peluso, Ivana, Soldati, Chiara, Napolitano, Gennaro, Matarese, Maria, Heras, Macarena Las, Valls, Cristian, Martinez, Alexis, Balboa, Elisa, Castro, Juan, Leal, Nancy, Platt, Frances M., Sobota, Andrzej, Winter, Dominic, Klein, Andrés D., Medina, Diego L., Ballabio, Andrea, Alvarez, Alejandra R., Zanlungo, Silvana
Format: Article
Language:English
Subjects:
Biological Sciences
Cell Biology
Molecular Biology
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Summary:The 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. [Display omitted] •c-Abl is a TFEB regulator that mediates its tyr phosphorylation•c-Abl inhibition promotes TFEB activity independently of mTORC1•c-Abl inhibition reduces cholesterol accumulation in NPC1 models Biological Sciences; Molecular Biology; Cell Biology
ISSN:2589-0042
2589-0042
DOI:10.1016/j.isci.2020.101691