An mTORC1-to-CDK1 Switch Maintains Autophagy Suppression during Mitosis.

Richard I Odle, Simon A Walker, David Oxley, Andrew M Kidger, Kathryn Balmanno, Rebecca Gilley, Hanneke Okkenhaug, Oliver Florey, Nicholas T Ktistakis, Simon J Cook

Molecular cell 2020 Jan 16

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Since nuclear envelope breakdown occurs during mitosis in metazoan cells, it has been proposed that macroautophagy must be inhibited to maintain genome integrity. However, repression of macroautophagy during mitosis remains controversial and mechanistic detail limited to the suggestion that CDK1 phosphorylates VPS34. Here, we show that initiation of macroautophagy, measured by the translocation of the ULK complex to autophagic puncta, is repressed during mitosis, even when mTORC1 is inhibited. Indeed, mTORC1 is inactive during mitosis, reflecting its failure to localize to lysosomes due to CDK1-dependent RAPTOR phosphorylation. While mTORC1 normally represses autophagy via phosphorylation of ULK1, ATG13, ATG14, and TFEB, we show that the mitotic phosphorylation of these autophagy regulators, including at known repressive sites, is dependent on CDK1 but independent of mTOR. Thus, CDK1 substitutes for inhibited mTORC1 as the master regulator of macroautophagy during mitosis, uncoupling autophagy regulation from nutrient status to ensure repression of macroautophagy during mitosis. Crown Copyright © 2019. Published by Elsevier Inc. All rights reserved.

Citation

Richard I Odle, Simon A Walker, David Oxley, Andrew M Kidger, Kathryn Balmanno, Rebecca Gilley, Hanneke Okkenhaug, Oliver Florey, Nicholas T Ktistakis, Simon J Cook. An mTORC1-to-CDK1 Switch Maintains Autophagy Suppression during Mitosis. Molecular cell. 2020 Jan 16;77(2):228-240.e7