Nuclear Export Inhibition Enhances HLH-30/TFEB Activity, Autophagy, and Lifespan.
Cell Rep
; 23(7): 1915-1921, 2018 05 15.
Article
em En
| MEDLINE
| ID: mdl-29768192
ABSTRACT
Transcriptional modulation of the process of autophagy involves the transcription factor HLH-30/TFEB. In order to systematically determine the regulatory network of HLH-30/TFEB, we performed a genome-wide RNAi screen in C. elegans and found that silencing the nuclear export protein XPO-1/XPO1 enhances autophagy by significantly enriching HLH-30 in the nucleus, which is accompanied by proteostatic benefits and improved longevity. Lifespan extension via xpo-1 silencing requires HLH-30 and autophagy, overlapping mechanistically with several established longevity models. Selective XPO1 inhibitors recapitulated the effect on autophagy and lifespan observed by silencing xpo-1 and protected ALS-afflicted flies from neurodegeneration. XPO1 inhibition in HeLa cells enhanced TFEB nuclear localization, autophagy, and lysosome biogenesis without affecting mTOR activity, revealing a conserved regulatory mechanism for HLH-30/TFEB. Altogether, our study demonstrates that altering the nuclear export of HLH-30/TFEB can regulate autophagy and establishes the rationale of targeting XPO1 to stimulate autophagy in order to prevent neurodegeneration.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Autofagia
/
Núcleo Celular
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Caenorhabditis elegans
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Proteínas de Caenorhabditis elegans
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Fatores de Transcrição Hélice-Alça-Hélice Básicos
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Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos
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Longevidade
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Revista:
Cell Rep
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Estados Unidos