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

Contreras, Pablo; Tapia, José Pablo; Gonzalez-Hodar, L; Peluso, Ivana; Soldati, Chiara; Napolitano, Gennaro; Matarese, Maria; Las Heras, Macarena; Valls, Cristian; Martinez, Alexis; Balboa, Elisa; Castro, Juan; Leal, Nancy; Platt, Frances M; Sobota, Andrzej; et. al.


The transcription factor EB (TFEB) has emerged as a master regulator of lyso- somal biogenesis, exocytosis, and autophagy, promoting the clearance of sub- strates 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 lyso- somal 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 choles- terol clearance in NPC models.

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Título de la Revista: iScience
Volumen: 23
Número: 11
Editorial: Sciencedirect
Fecha de publicación: 2020
Página de inicio: 1
Página final: 21
Idioma: Inglés
URL: https://www.sciencedirect.com/science/article/pii/S258900422030883X


Notas: ISI