| First Author | Contreras PS | Year | 2020 |
| Journal | iScience | Volume | 23 |
| Issue | 11 | Pages | 101691 |
| PubMed ID | 33163944 | Mgi Jnum | J:312846 |
| Mgi Id | MGI:6717486 | Doi | 10.1016/j.isci.2020.101691 |
| Citation | Contreras PS, et al. (2020) c-Abl Inhibition Activates TFEB and Promotes Cellular Clearance in a Lysosomal Disorder. iScience 23(11):101691 |
| abstractText | 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. |
