An mTORC1-to-CDK1 Switch Maintains Autophagy Suppression during Mitosis
Richard I Odle1, Simon A Walker2, David Oxley3
1Signalling Laboratory, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.
Molecular Cell
|November 18, 2019
Summary
Macroautophagy initiation is repressed during mitosis. Cell division kinase 1 (CDK1) directly inhibits macroautophagy by phosphorylating key regulators, overriding nutrient signaling to maintain genome integrity.
Area of Science:
- Cell Biology
- Molecular Biology
- Autophagy Research
Background:
- Nuclear envelope breakdown during mitosis suggests macroautophagy inhibition is necessary for genome integrity.
- The mechanism of mitotic macroautophagy repression is not fully understood, with CDK1 phosphorylation of VPS34 being a proposed but unconfirmed pathway.
Purpose of the Study:
- To investigate the regulation of macroautophagy during mitosis.
- To elucidate the molecular mechanisms controlling macroautophagy initiation in dividing cells.
Main Methods:
- Monitoring ULK complex translocation to autophagic puncta as a measure of macroautophagy initiation.
- Assessing mTORC1 localization and activity during mitosis.
- Analyzing the phosphorylation status of autophagy regulators (ULK1, ATG13, ATG14, TFEB) during mitosis.
- Investigating the role of CDK1 and mTORC1 in regulating these phosphorylation events.
Main Results:
- Macroautophagy initiation is repressed during mitosis, irrespective of mTORC1 inhibition.
- mTORC1 is inactive during mitosis due to CDK1-dependent RAPTOR phosphorylation, preventing lysosomal localization.
- CDK1, not mTORC1, directly phosphorylates key autophagy regulators (ULK1, ATG13, ATG14, TFEB) at repressive sites during mitosis.
Conclusions:
- CDK1 acts as the master regulator of macroautophagy during mitosis, substituting for the inactive mTORC1.
- Mitotic autophagy repression is uncoupled from nutrient status, ensuring genome integrity through CDK1-mediated inhibition.
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