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

Ki Eun Pyo1, Chang Rok Kim1, Minkyoung Lee1

  • 1Creative Research Initiatives Center for Epigenetic Code and Diseases, Department of Biological Sciences, Seoul National University, Seoul 08826, South Korea.

Cell Reports
|December 6, 2018
PubMed

Insights

Unc-51-like-kinase 1 (ULK1) becomes O-GlcNAcylated upon glucose starvation, a critical step for autophagy initiation. This modification is essential for activating autophagy-related proteins and promoting phagophore formation.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Unc-51-like-kinase 1 (ULK1) regulates autophagy initiation, responding to nutrient cues like glucose starvation.
  • ULK1 activity is modulated by mechanistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK).

Purpose of the Study:

  • To investigate the role of O-linked N-acetylglucosamine (O-GlcNAcylation) in ULK1 regulation during glucose starvation.
  • To elucidate the molecular mechanism linking O-GlcNAcylation to autophagy initiation.

Main Methods:

  • Western blotting to detect protein modifications (phosphorylation, O-GlcNAcylation).
  • Co-immunoprecipitation assays to study protein-protein interactions.
  • In vitro kinase assays to assess enzyme activity.

Main Results:

  • ULK1 undergoes O-GlcNAcylation at Threonine 754 by O-linked N-acetylglucosamine transferase (OGT) upon glucose starvation.
  • O-GlcNAcylation occurs after dephosphorylation of Serine 757 (mTOR-dependent) and phosphorylation by AMPK.
  • ULK1 O-GlcNAcylation is required for binding and phosphorylating ATG14L, activating VPS34 and phosphatidylinositol-(3)-phosphate (PI(3)P) production for autophagy initiation.

Conclusions:

  • O-GlcNAcylation of ULK1 is a key regulatory event in autophagy initiation under starvation conditions.
  • This study reveals a crosstalk between dephosphorylation and O-GlcNAcylation in controlling autophagy.
  • The findings offer a molecular framework for therapeutic strategies targeting autophagy-related diseases.
Keywords:
AMPKO-GlcNACylationPP1ULK1autophagy initiationmTORC1phagophore formation

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