puc-header

c-Abl Inhibition Activates TFEB: A Novel Way To Promote Cellular Clearance in Lysosomal Disorders

66 Pages Posted: 4 Aug 2020 Publication Status: Published

See all articles by Pablo S. Contreras

Pablo S. Contreras

Pontificia Universidad Católica de Chile - Department of Cell & Molecular Biology

Pablo J. Tapia

Pontificia Universidad Católica de Chile - Department of Gastroenterology

Lila González-Hódar

Pontificia Universidad Católica de Chile - Department of Gastroenterology

Ivana Peluso

Telethon Institute of Genetics and Medicine (TIGEM)

Chiara Soldati

Telethon Institute of Genetics and Medicine (TIGEM)

Gennaro Napolitano

Telethon Institute of Genetics and Medicine (TIGEM)

Maria Matarese

Telethon Institute of Genetics and Medicine (TIGEM)

Macarena Las Heras

Pontificia Universidad Católica de Chile - Department of Gastroenterology

Cristian Valls

Pontificia Universidad Católica de Chile - Department of Cell & Molecular Biology

Alexis Martinez

Pontificia Universidad Católica de Chile - Department of Cell & Molecular Biology

Elisa Balboa

Pontificia Universidad Católica de Chile - Department of Gastroenterology

Juan Castro

Pontificia Universidad Católica de Chile - Department of Gastroenterology

Nancy Leal

Pontificia Universidad Católica de Chile - Department of Cell & Molecular Biology

Frances M. Platt

University of Oxford - Department of Pharmacology

Andrzej Sobota

Nencki Institute of Experimental Biology - Department of Cell Biology

Dominic Winter

Rheinische-Friedrich-Wilhelms-University - Institute for Biochemistry and Molecular Biology

Andrés D. Klein

Universidad del desarrollo Clínica Alemana de Santiago - Centro de Genética y Genómica

Diego L. Medina

Telethon Institute of Genetics and Medicine (TIGEM)

Andrea Ballabio

Telethon Institute of Genetics and Medicine (TIGEM)

Alejandra R. Alvarez

Pontificia Universidad Católica de Chile - Department of Cell & Molecular Biology

Silvana Zanlungo

Pontificia Universidad Católica de Chile - Department of Gastroenterology

More...

Abstract

Lysosomes fulfill multiple functions involved in cellular homeostasis and their dysfunction leads to substrates accumulation causing neurodegenerative diseases. 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, mTORC1. Active c-Abl induces TFEB phosphorylation on tyrosine and the inhibition of this kinase promotes lysosomal biogenesis, autophagy and exocytosis. c-Abl inhibition in pharmacological 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. In genetic NPC models, c-Abl inhibition promotes cellular clearance through TFEB activation. We propose the modulation of this novel c-Abl/TFEB axis, using the FDA-approved drugs Imatinib or Nilotinib, as a therapeutic strategy to treat different neurodegenerative storage disorders.

Keywords: Tyrosine kinase c-Abl, Transcription Factor EB (TFEB), Niemann-Pick type C (NPC), Lysosomal Storage Disorders (LSD), Cellular clearance, Autophagy

Suggested Citation

Contreras, Pablo S. and Tapia, Pablo J. and González-Hódar, Lila and Peluso, Ivana and Soldati, Chiara and Napolitano, Gennaro and Matarese, Maria and Las Heras, Macarena and Valls, Cristian and Martinez, Alexis and Balboa, Elisa and Castro, Juan and Leal, Nancy and Platt, Frances M. and Sobota, Andrzej and Winter, Dominic and Klein, Andrés D. and Medina, Diego L. and Ballabio, Andrea and Alvarez, Alejandra R. and Zanlungo, Silvana, c-Abl Inhibition Activates TFEB: A Novel Way To Promote Cellular Clearance in Lysosomal Disorders. Available at SSRN: https://ssrn.com/abstract=3646566 or http://dx.doi.org/10.2139/ssrn.3646566
This version of the paper has not been formally peer reviewed.

Pablo S. Contreras

Pontificia Universidad Católica de Chile - Department of Cell & Molecular Biology ( email )

Chile

Pablo J. Tapia

Pontificia Universidad Católica de Chile - Department of Gastroenterology ( email )

Chile

Lila González-Hódar

Pontificia Universidad Católica de Chile - Department of Gastroenterology ( email )

Chile

Ivana Peluso

Telethon Institute of Genetics and Medicine (TIGEM) ( email )

Chiara Soldati

Telethon Institute of Genetics and Medicine (TIGEM) ( email )

Gennaro Napolitano

Telethon Institute of Genetics and Medicine (TIGEM) ( email )

Maria Matarese

Telethon Institute of Genetics and Medicine (TIGEM) ( email )

Macarena Las Heras

Pontificia Universidad Católica de Chile - Department of Gastroenterology ( email )

Chile

Cristian Valls

Pontificia Universidad Católica de Chile - Department of Cell & Molecular Biology ( email )

Chile

Alexis Martinez

Pontificia Universidad Católica de Chile - Department of Cell & Molecular Biology ( email )

Chile

Elisa Balboa

Pontificia Universidad Católica de Chile - Department of Gastroenterology ( email )

Chile

Juan Castro

Pontificia Universidad Católica de Chile - Department of Gastroenterology ( email )

Chile

Nancy Leal

Pontificia Universidad Católica de Chile - Department of Cell & Molecular Biology ( email )

Chile

Frances M. Platt

University of Oxford - Department of Pharmacology ( email )

United Kingdom

Andrzej Sobota

Nencki Institute of Experimental Biology - Department of Cell Biology ( email )

Dominic Winter

Rheinische-Friedrich-Wilhelms-University - Institute for Biochemistry and Molecular Biology ( email )

Andrés D. Klein

Universidad del desarrollo Clínica Alemana de Santiago - Centro de Genética y Genómica ( email )

Diego L. Medina

Telethon Institute of Genetics and Medicine (TIGEM) ( email )

Andrea Ballabio

Telethon Institute of Genetics and Medicine (TIGEM)

Alejandra R. Alvarez

Pontificia Universidad Católica de Chile - Department of Cell & Molecular Biology ( email )

Chile

Silvana Zanlungo (Contact Author)

Pontificia Universidad Católica de Chile - Department of Gastroenterology ( email )

Chile

Click here to go to Cell.com

Paper statistics

Downloads
14
Abstract Views
380
PlumX Metrics