Lysosomal calcium signalling regulates autophagy through calcineurin and âTFEB.
Nat Cell Biol
; 17(3): 288-99, 2015 Mar.
Article
em En
| MEDLINE
| ID: mdl-25720963
ABSTRACT
The view of the lysosome as the terminal end of cellular catabolic pathways has been challenged by recent studies showing a central role of this organelle in the control of cell function. Here we show that a lysosomal Ca2+ signalling mechanism controls the activities of the phosphatase calcineurin and of its substrate âTFEB, a master transcriptional regulator of lysosomal biogenesis and autophagy. Lysosomal Ca2+ release through âmucolipin 1 (âMCOLN1) activates calcineurin, which binds and dephosphorylates âTFEB, thus promoting its nuclear translocation. Genetic and pharmacological inhibition of calcineurin suppressed âTFEB activity during starvation and physical exercise, while calcineurin overexpression and constitutive activation had the opposite effect. Induction of autophagy and lysosomal biogenesis through âTFEB required âMCOLN1-mediated calcineurin activation. These data link lysosomal calcium signalling to both calcineurin regulation and autophagy induction and identify the lysosome as a hub for the signalling pathways that regulate cellular homeostasis.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Autofagia
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Calcineurina
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Canais de Potencial de Receptor Transitório
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Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos
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Lisossomos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article