LC3 lipidation is essential for TFEB activation during the lysosomal damage response to kidney injury.
Nat Cell Biol
; 22(10): 1252-1263, 2020 10.
Article
em En
| MEDLINE
| ID: mdl-32989250
ABSTRACT
Sensing and clearance of dysfunctional lysosomes is critical for cellular homeostasis. Here we show that transcription factor EB (TFEB)-a master transcriptional regulator of lysosomal biogenesis and autophagy-is activated during the lysosomal damage response, and its activation is dependent on the function of the ATG conjugation system, which mediates LC3 lipidation. In addition, lysosomal damage triggers LC3 recruitment on lysosomes, where lipidated LC3 interacts with the lysosomal calcium channel TRPML1, facilitating calcium efflux essential for TFEB activation. Furthermore, we demonstrate the presence and importance of this TFEB activation mechanism in kidneys in a mouse model of oxalate nephropathy accompanying lysosomal damage. A proximal tubule-specific TFEB-knockout mouse exhibited progression of kidney injury induced by oxalate crystals. Together, our results reveal unexpected mechanisms of TFEB activation by LC3 lipidation and their physiological relevance during the lysosomal damage response.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Autofagia
/
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos
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Injúria Renal Aguda
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Lipídeos
/
Lisossomos
/
Proteínas Associadas aos Microtúbulos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
Nat Cell Biol
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Japão