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ULK1 O-GlcNAcylation is crucial for activating VPS34 via ATG14L during autophagy initiation

Cited 46 time in Web of Science Cited 47 time in Scopus
Authors

Pyo, Ki Eun; Kim, Chang Rok; Lee, Minkyoung; Kim, Jong-Seo; Kim, Keun Il; Baek, Sung Hee

Issue Date
2018-12
Publisher
Cell Press
Citation
Cell Reports, Vol.25 No.10, pp.2878-+
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.
ISSN
2211-1247
URI
https://hdl.handle.net/10371/201889
DOI
https://doi.org/10.1016/j.celrep.2018.11.042
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  • College of Natural Sciences
  • School of Biological Sciences
Research Area Molecular Interactomics, Proteomics, Systems Biology, 단백체학, 분자상호작용체학, 시스템생물학

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