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

Pablo S Contreras; Pablo J Tapia; Lila González-Hódar; Ivana Peluso; Chiara Soldati; Gennaro Napolitano; Maria Matarese; Macarena Las Heras; Cristian Valls; Alexis Martinez; Elisa Balboa; Juan Castro; Nancy Leal; Frances M Platt; Andrzej Sobota; Dominic Winter; Andrés D Klein; Diego L Medina; Andrea Ballabio; Alejandra R Alvarez; Silvana Zanlungo

doi:10.1016/j.isci.2020.101691

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

iScience. 2020 Oct 15;23(11):101691. doi: 10.1016/j.isci.2020.101691. eCollection 2020 Nov 20.

Authors

Pablo S Contreras^{1

2

3}, Pablo J Tapia³, Lila González-Hódar³, Ivana Peluso⁴, Chiara Soldati⁴, Gennaro Napolitano⁴, Maria Matarese⁴, Macarena Las Heras³, Cristian Valls^{1

2}, Alexis Martinez^{1

2}, Elisa Balboa³, Juan Castro³, Nancy Leal^{1

2}, Frances M Platt⁵, Andrzej Sobota⁶, Dominic Winter⁷, Andrés D Klein⁸, Diego L Medina⁴, Andrea Ballabio^{4

9

10

11}, Alejandra R Alvarez^{1

2}, Silvana Zanlungo³

Affiliations

¹ Department of Cell & Molecular Biology, Biological Sciences Faculty, Pontificia Universidad Católica de Chile, Alameda 340, Santiago 8331010, Chile.
² CARE UC Pontificia Universidad Católica de Chile, Santiago, Chile.
³ Department of Gastroenterology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Alameda 340, Santiago 8331010, Chile.
⁴ Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, 80078 Pozzuoli, Naples, Italy.
⁵ Department of Pharmacology, University of Oxford, Oxford, UK.
⁶ Department of Cell Biology, Nencki Institute of Experimental Biology, 3 Pasteur St., 02-093 Warsaw, Poland.
⁷ Institute for Biochemistry and Molecular Biology, Rheinische-Friedrich-Wilhelms-University, Bonn, Germany.
⁸ Centro de Genética y Genómica, Universidad Del Desarrollo Clínica Alemana de Santiago, Chile.
⁹ Medical Genetics, Department of Pediatrics, Federico II University, Via Pansini 5, 80131 Naples, Italy.
¹⁰ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
¹¹ Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.

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.

Keywords: Biological Sciences; Cell Biology; Molecular Biology.