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Study of Protein-protein Interactions in Autophagy Research
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Study of Protein-protein Interactions in Autophagy Research

Published on: September 9, 2017

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The ULK1 complex mediates MTORC1 signaling to the autophagy initiation machinery via binding and phosphorylating

Ji-Man Park1, Chang Hwa Jung1,2, Minchul Seo1

  • 1a Department of Biochemistry, Molecular Biology, and Biophysics , University of Minnesota , Minneapolis , MN , USA.

Autophagy
|April 6, 2016
PubMed

Insights

Unc-51 like autophagy activating kinase 1 (ULK1) activates autophagy by phosphorylating ATG14, a key step in phagophore formation. This phosphorylation is crucial for initiating autophagosome biogenesis under starvation conditions.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Autophagy Research

Background:

  • Unc-51 like autophagy activating kinase 1 (ULK1) is central to MTORC1 signaling and autophagy induction.
  • The precise mechanism by which ULK1 initiates autophagosome formation remains unclear.

Purpose of the Study:

  • To elucidate the role of ULK1 in regulating autophagy induction.
  • To identify the molecular events linking ULK1 activity to the autophagosome formation machinery.

Main Methods:

  • Investigated protein-protein interactions using ULK1 and ATG13 as binding partners.
  • Analyzed the phosphorylation of ATG14 by ULK1 under various nutrient conditions.
  • Utilized genetic manipulation to assess the requirement of specific autophagy proteins (BECN1, ATG9A) and complexes (PIK3C3/VPS34).
  • Monitored ATG14 phosphorylation in vivo to correlate with dietary conditions.

Main Results:

  • ATG13 mediates the interaction between ULK1 and the ATG14-containing PIK3C3/VPS34 complex.
  • ULK1 phosphorylates ATG14 under starvation or MTORC1 inhibition, enhancing class III phosphatidylinositol 3-kinase (PtdIns3K) activity.
  • ATG14 phosphorylation facilitates phagophore and autophagosome formation.
  • ULK1 activity requires BECN1 but not PE-conjugation or PIK3C3 kinase activity for ATG14 phosphorylation.
  • ATG9A suppresses ULK1 activity under nutrient-rich conditions.
  • ATG14 phosphorylation is dependent on ULK1 and dietary conditions in vivo.

Conclusions:

  • Defined a critical molecular event: ULK1-mediated ATG14 phosphorylation activates the PtdIns3K complex during starvation-induced autophagy.
  • Established a hierarchical relationship between ULK1 activation and other autophagy proteins in phagophore formation.
Keywords:
ATG13ATG14BECN1MTORC1PIK3C3ULK1

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