c-Abl Inhibition Activates TFEB and Promotes Cellular Clearance in a Lysosomal Disorder
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 conditio...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-11-01
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| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S258900422030883X |
| _version_ | 1818149411409100800 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Pablo S. Contreras |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-11T13:06:37Z |
| format | Article |
| id | doaj.art-c6a46857605147c4a1da866ca411c8d6 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-12-11T13:06:37Z |
| publishDate | 2020-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-c6a46857605147c4a1da866ca411c8d62022-12-22T01:06:18ZengElsevieriScience2589-00422020-11-012311101691c-Abl Inhibition Activates TFEB and Promotes Cellular Clearance in a Lysosomal DisorderPablo S. Contreras0Pablo J. Tapia1Lila González-Hódar2Ivana Peluso3Chiara Soldati4Gennaro Napolitano5Maria Matarese6Macarena Las Heras7Cristian Valls8Alexis Martinez9Elisa Balboa10Juan Castro11Nancy Leal12Frances M. Platt13Andrzej Sobota14Dominic Winter15Andrés D. Klein16Diego L. Medina17Andrea Ballabio18Alejandra R. Alvarez19Silvana Zanlungo20Department of Cell & Molecular Biology, Biological Sciences Faculty, Pontificia Universidad Católica de Chile, Alameda 340, Santiago 8331010, Chile; CARE UC Pontificia Universidad Católica de Chile, Santiago, Chile; Department of Gastroenterology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Alameda 340, Santiago 8331010, ChileDepartment of Gastroenterology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Alameda 340, Santiago 8331010, ChileDepartment of Gastroenterology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Alameda 340, Santiago 8331010, ChileTelethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, 80078 Pozzuoli, Naples, ItalyTelethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, 80078 Pozzuoli, Naples, ItalyTelethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, 80078 Pozzuoli, Naples, ItalyTelethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, 80078 Pozzuoli, Naples, ItalyDepartment of Gastroenterology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Alameda 340, Santiago 8331010, ChileDepartment of Cell & Molecular Biology, Biological Sciences Faculty, Pontificia Universidad Católica de Chile, Alameda 340, Santiago 8331010, Chile; CARE UC Pontificia Universidad Católica de Chile, Santiago, ChileDepartment of Cell & Molecular Biology, Biological Sciences Faculty, Pontificia Universidad Católica de Chile, Alameda 340, Santiago 8331010, Chile; CARE UC Pontificia Universidad Católica de Chile, Santiago, ChileDepartment of Gastroenterology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Alameda 340, Santiago 8331010, ChileDepartment of Gastroenterology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Alameda 340, Santiago 8331010, ChileDepartment of Cell & Molecular Biology, Biological Sciences Faculty, Pontificia Universidad Católica de Chile, Alameda 340, Santiago 8331010, Chile; CARE UC Pontificia Universidad Católica de Chile, Santiago, ChileDepartment of Pharmacology, University of Oxford, Oxford, UKDepartment of Cell Biology, Nencki Institute of Experimental Biology, 3 Pasteur St., 02-093 Warsaw, PolandInstitute for Biochemistry and Molecular Biology, Rheinische-Friedrich-Wilhelms-University, Bonn, GermanyCentro de Genética y Genómica, Universidad Del Desarrollo Clínica Alemana de Santiago, ChileTelethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, 80078 Pozzuoli, Naples, ItalyTelethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, 80078 Pozzuoli, Naples, Italy; Medical Genetics, Department of Pediatrics, Federico II University, Via Pansini 5, 80131 Naples, Italy; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USADepartment of Cell & Molecular Biology, Biological Sciences Faculty, Pontificia Universidad Católica de Chile, Alameda 340, Santiago 8331010, Chile; CARE UC Pontificia Universidad Católica de Chile, Santiago, Chile; Corresponding authorDepartment of Gastroenterology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Alameda 340, Santiago 8331010, Chile; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S258900422030883XBiological SciencesMolecular BiologyCell Biology |
| spellingShingle | 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 c-Abl Inhibition Activates TFEB and Promotes Cellular Clearance in a Lysosomal Disorder iScience Biological Sciences Molecular Biology Cell Biology |
| title | c-Abl Inhibition Activates TFEB and Promotes Cellular Clearance in a Lysosomal Disorder |
| title_full | c-Abl Inhibition Activates TFEB and Promotes Cellular Clearance in a Lysosomal Disorder |
| title_fullStr | c-Abl Inhibition Activates TFEB and Promotes Cellular Clearance in a Lysosomal Disorder |
| title_full_unstemmed | c-Abl Inhibition Activates TFEB and Promotes Cellular Clearance in a Lysosomal Disorder |
| title_short | c-Abl Inhibition Activates TFEB and Promotes Cellular Clearance in a Lysosomal Disorder |
| title_sort | c abl inhibition activates tfeb and promotes cellular clearance in a lysosomal disorder |
| topic | Biological Sciences Molecular Biology Cell Biology |
| url | http://www.sciencedirect.com/science/article/pii/S258900422030883X |
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