Browsing by Author "Valls, Cristian"
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Item c-Abl Inhibition Activates TFEB and Promotes Cellular Clearance in a Lysosomal Disorder(Cell Press, 2020) Contreras, Pablo; Tapia, Pablo; González-Hodar, Lila; Peluso, Ivana; Soldati, Chiara; Napoiotano, Gennaro; Matarese, María; Las Heras, Macarena; Valls, Cristian; Martínez, Alexis; Balboa, Elisa; Castro, Juan; Nancy, Leal; Platt, Frances; Sobota, Andrzej; Winter, Dominic; Klein, Andrés; Medina, Diego; Ballabio, Andrea; Alvarez, Alejandra; Zanlungo, SilvanaThe 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.