Journal
ISCIENCE
Volume 23, Issue 11, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.isci.2020.101691
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Funding
- Fondo Nacional de Desarrollo Cientifico y Tecnologico (FONDECYT) [1161065, 1201668, 1150186, 1190334]
- CONICYT-Chile Grant Redes [150082]
- University of Pennsylvania Orphan Disease Center
- European Union's Horizon 2020 research and innovation program (RISE) under the Marie Sklodowska-Curie grant [734825]
- Fomento al Desarrollo Cientifico y Tecnologico [FONDEF D10E1077]
- CONICYT, Beca doctorado nacional [21140469]
- Advanced Microscopy Facility UC
- PIA CONICYT [ECM-07]
- [AFB170005]
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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 TFEBdependent 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.
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