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ULK1 O-GlcNAcylation Is Crucial for Activating VPS34 via ATG14L during Autophagy Initiation

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Title
ULK1 O-GlcNAcylation Is Crucial for Activating VPS34 via ATG14L during Autophagy Initiation
Author(s)
Ki Eun Pyo; Chang Rok Kim; Minkyoung Lee; Jong-Seo Kim; Keun Il Kim; Sung Hee Baek
Publication Date
2018-12
Journal
CELL REPORTS, v.25, no.10, pp.2878 - 2.89E+07
Publisher
CELL PRESS
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. Autophagy initiation is regulated by ULK1, a serine/threonine kinase. Pyo et al. demonstrate that ULK1 is O-GlcNAcylated on threonine 754 by OGT upon glucose starvation. O-GlcNAcylation of ULK1 is crucial for activating VPS34 via ATG14L. Our findings provide new insights into the crosstalk between dephosphorylation and O-GlcNAcylation during the autophagy process. c. 2018 The Author(s)
URI
https://pr.ibs.re.kr/handle/8788114/5315
ISSN
2211-1247
Appears in Collections:
Center for RNA Research(RNA 연구단) > Journal Papers (저널논문)
Files in This Item:
PIIS2211124718318059.pdfDownload

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