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ULK1-ATG13 and their mitotic phospho-regulation by CDK1 connect autophagy to cell cycle

Zhiyuan Li1, Xiaofei Tian1, Xinmiao Ji1

  • 1High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, P. R. China.

Plos Biology
|June 10, 2020
PubMed

Insights

The Unc-51-like autophagy activating kinase 1 (ULK1)-autophagy-related 13 (ATG13) complex drives cell cycle progression and cancer proliferation. Its phosphorylation by cyclin-dependent kinase 1 (CDK1) during mitosis promotes essential cell functions.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Autophagy Research

Background:

  • The Unc-51-like autophagy activating kinase 1 (ULK1)-autophagy-related 13 (ATG13) complex initiates autophagy, regulated by mTORC1 and AMPK in asynchronous cells.
  • The role of ULK1-ATG13 phosphorylation and function during mitosis and the cell cycle is largely unknown.

Purpose of the Study:

  • To investigate the phospho-regulation and functional significance of the ULK1-ATG13 complex during mitosis and cell cycle progression.
  • To elucidate the role of cyclin-dependent kinase 1 (CDK1) in regulating ULK1-ATG13 phosphorylation and its impact on mitotic autophagy.

Main Methods:

  • Utilized mass spectrometry to identify phosphorylation sites on ULK1 and ATG13.
  • Employed site-directed mutagenesis to study the functional consequences of CDK1-mediated phosphorylation.
  • Generated ULK1 and ATG13 double knockout (DKO) models in cell lines and mice.

Main Results:

  • ULK1-ATG13 complex exhibits differential regulation throughout the cell cycle, with high phosphorylation during mitosis by CDK1/cyclin B.
  • CDK1-induced phosphorylation of ULK1-ATG13 promotes mitotic autophagy and facilitates cell cycle progression.
  • ULK1/ATG13 DKO significantly impairs cell cycle progression and reduces cancer cell proliferation.

Conclusions:

  • The ULK1-ATG13 complex is a key regulator of mitotic autophagy and cell cycle progression.
  • CDK1-mediated phosphorylation of ULK1-ATG13 plays a crucial role in linking autophagy and mitosis.
  • Targeting ULK1-ATG13 phosphorylation presents a potential strategy for cancer therapy.

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