c-Abl Inhibition Activates TFEB and Promotes Cellular Clearance in a Lysosomal Disorder
Pablo S. Contreras, Pablo Tapía, Lila González-Hódar, Ivana Peluso, Chiara Soldati, Gennaro Napolitano, Maria Matarese, Macarena Las Heras, Cristian Valls, Alexis Martínez, Elisa Balboa, Juan Francisco Castro, Nancy Leal, Frances M. Platt, Andrzej Sobota, Dominic Winter, Andrés D. Klein, Diego L. Medina, Andrea Ballabio, Alejandra Álvarez, Silvana Zanlungo
Abstract
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.