文章基本信息

标题：c-Abl Inhibition Activates TFEB and Promotes Cellular Clearance in a Lysosomal Disorder
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作者：Pablo S. Contreras ; Pablo J. Tapia ; Lila González-Hódar 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2020
卷号：23
期号：11
页码：1-40
DOI：10.1016/j.isci.2020.101691
语种：English
出版社：Elsevier
摘要：SummaryThe 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.Graphical AbstractDisplay OmittedHighlights•c-Abl is a TFEB regulator that mediates its tyr phosphorylation•c-Abl inhibition promotes TFEB activity independently of mTORC1•c-Abl inhibition reduces cholesterol accumulation in NPC1 modelsBiological Sciences; Molecular Biology; Cell Biology