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

iScience

Lila González-Hódar¹  Andrés D. Klein¹  Frances M. Platt¹  Ivana Peluso²  Nancy Leal³  Silvana Zanlungo³  Dominic Winter³  Pablo J. Tapia³  Pablo S. Contreras⁴  Alejandra R. Alvarez⁴  Juan Castro⁴  Andrzej Sobota⁴  Gennaro Napolitano⁵  Diego L. Medina⁵  Elisa Balboa⁵  Chiara Soldati⁵  Andrea Ballabio⁵  Macarena Las Heras⁶  Alexis Martinez⁶  Maria Matarese⁶  Cristian Valls⁶ 

[1] CARE UC Pontificia Universidad Católica de Chile, Santiago, Chile;Department of Gastroenterology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Alameda 340, Santiago 8331010, Chile;Molecular Biology, Biological Sciences Faculty, Pontificia Universidad Católica de Chile, Alameda 340, Santiago 8331010, Chile;;Department of Cell &Department of Gastroenterology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Alameda 340, Santiago 8331010, Chile;Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, 80078 Pozzuoli, Naples, Italy;

关键词: Biological Sciences;    Molecular Biology;    Cell Biology;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown