ULK1 O-GlcNAcylation Is Crucial for Activating VPS34 via ATG14L during Autophagy Initiation.
Cell Rep
; 25(10): 2878-2890.e4, 2018 12 04.
Article
en En
| MEDLINE
| ID: mdl-30517873
ABSTRACT
Unc-51-like-kinase 1 (ULK1) is a target of both the mechanistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK), whose role is to facilitate the initiation of autophagy in response to starvation. Upon glucose starvation, dissociation of mTOR from ULK1 and phosphorylation by AMPK leads to the activation of ULK1 activity. Here, we provide evidence that ULK1 is the attachment of O-linked N-acetylglucosamine (O-GlcNAcylated) on the threonine 754 site by O-linked N-acetylglucosamine transferase (OGT) upon glucose starvation. ULK1 O-GlcNAcylation occurs after dephosphorylation of adjacent mTOR-dependent phosphorylation on the serine 757 site by protein phosphatase 1 (PP1) and phosphorylation by AMPK. ULK1 O-GlcNAcylation is crucial for binding and phosphorylation of ATG14L, allowing the activation of lipid kinase VPS34 and leading to the production of phosphatidylinositol-(3)-phosphate (PI(3)P), which is required for phagophore formation and initiation of autophagy. Our findings provide insights into the crosstalk between dephosphorylation and O-GlcNAcylation during autophagy and specify a molecular framework for potential therapeutic intervention in autophagy-related diseases.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Autofagia
/
Proteínas Adaptadoras del Transporte Vesicular
/
Péptidos y Proteínas de Señalización Intracelular
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Fosfatidilinositol 3-Quinasas Clase III
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Homólogo de la Proteína 1 Relacionada con la Autofagia
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Proteínas Relacionadas con la Autofagia
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Glucosamina
Límite:
Humans
Idioma:
En
Revista:
Cell Rep
Año:
2018
Tipo del documento:
Article
País de afiliación:
Corea del Sur