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

Pyo, Ki Eun, Kim, Chang Rok, Lee, Minkyoung, Kim, Jong-Seo, Kim, Keun Il, Baek, Sung Hee·2018·Cell Reports
DOI 10.1016/j.celrep.2018.11.042
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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.

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Metadata

Authors
Pyo, K. E., Kim, C. R., Lee, M., Kim, J.-S., Kim, K. I., & Baek, S. H.
Venue
Cell Reports
Publisher
Elsevier BV
Published
2018-12
Volume
25
Issue
10
Pages
2878-2890.e4
ISSN
2211-1247
DOI
10.1016/j.celrep.2018.11.042
Cited by
86
References
6
Language
en
Licence
Funders
  • Research Center for Epigenetic Code and Diseases (NRF-2017R1A3B1023387)
  • Cellular Heterogeneity Research Center (NRF-2016R1A5A1011974)
  • Glycosylation Network Research Center (NRF-2016R1A5A1010764, IBS-R008-D1)
  • Ministry of Science and ICT

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