c-Abl inhibition activates TFEB and promotes cellular clearance in a lysosomal disorder
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 th...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Cell Press
2020
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| _version_ | 1826285233859723264 |
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| author | Contreras, PS Tapia, PJ González-Hódar, L Peluso, I Soldati, C Napolitano, G Matarese, M Heras, ML Valls, C Martinez, A Balboa, E Castro, J Leal, N Platt, FM Sobota, A Winter, D Klein, AD Medina, DL Ballabio, A Alvarez, AR Zanlungo, S |
| author_facet | Contreras, PS Tapia, PJ González-Hódar, L Peluso, I Soldati, C Napolitano, G Matarese, M Heras, ML Valls, C Martinez, A Balboa, E Castro, J Leal, N Platt, FM Sobota, A Winter, D Klein, AD Medina, DL Ballabio, A Alvarez, AR Zanlungo, S |
| author_sort | Contreras, PS |
| collection | OXFORD |
| description | 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 | 2024-03-07T01:25:47Z |
| format | Journal article |
| id | oxford-uuid:91eef4f2-55fd-4082-bc2e-08944c29c0e2 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T01:25:47Z |
| publishDate | 2020 |
| publisher | Cell Press |
| record_format | dspace |
| spelling | oxford-uuid:91eef4f2-55fd-4082-bc2e-08944c29c0e22022-03-26T23:22:02Zc-Abl inhibition activates TFEB and promotes cellular clearance in a lysosomal disorderJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:91eef4f2-55fd-4082-bc2e-08944c29c0e2EnglishSymplectic ElementsCell Press2020Contreras, PSTapia, PJGonzález-Hódar, LPeluso, ISoldati, CNapolitano, GMatarese, MHeras, MLValls, CMartinez, ABalboa, ECastro, JLeal, NPlatt, FMSobota, AWinter, DKlein, ADMedina, DLBallabio, AAlvarez, ARZanlungo, SThe 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. |
| spellingShingle | Contreras, PS Tapia, PJ González-Hódar, L Peluso, I Soldati, C Napolitano, G Matarese, M Heras, ML Valls, C Martinez, A Balboa, E Castro, J Leal, N Platt, FM Sobota, A Winter, D Klein, AD Medina, DL Ballabio, A Alvarez, AR Zanlungo, S c-Abl inhibition activates TFEB and promotes cellular clearance in a lysosomal disorder |
| 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 |
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