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

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

doi:10.1016/j.molcel.2019.10.016

Cited by 89 publications

(117 citation statements)

References 76 publications

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“…Although it is well known that mTOR and AMPK phosphorylate ULK1/ATG13 in asynchronous cells [18,19], we found that mTOR or AMPK inhibition did not affect ULK1/ATG13 band shift in mitosis. In fact, it should be mentioned that although our preprint manuscript (BioRxiv on May 2019) was in revision in this journal, Odle and colleagues published a work also showing that CDK1 could phosphorylate ULK1 and ATG13 in mitosis [63]. They performed in vitro assays and identified phosphorylation sites using a short truncation of ULK1 or ATG13 and proposed that CDK1 could substitute mTOR to phosphorylate ULK1/ATG13.…”

Section: Ulk1/atg13 Phosphorylation By Mtor Ampk and Cdk1mentioning

confidence: 99%

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

Tian

et al. 2020

PLoS Biol

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Unc-51-like autophagy activating kinase 1 (ULK1)-autophagy-related 13 (ATG13) is the most upstream autophagy initiation complex that is phosphorylated by mammalian targetof-rapamycin complex 1 (mTORC1) and AMP-activated protein kinase (AMPK) to induce autophagy in asynchronous conditions. However, their phospho-regulation and functions in mitosis and cell cycle remain unknown. Here we show that ULK1-ATG13 complex is differentially regulated throughout the cell cycle, especially in mitosis, in which both ULK1 and ATG13 are highly phosphorylated by the key cell cycle machinery cyclin-dependent kinase 1 (CDK1)/cyclin B. Combining mass spectrometry and site-directed mutagenesis, we found that CDK1-induced ULK1-ATG13 phosphorylation promotes mitotic autophagy and cell cycle progression. Moreover, double knockout (DKO) of ULK1 and ATG13 could block cell cycle progression and significantly decrease cancer cell proliferation in cell line and mouse models. Our results not only bridge the mutual regulation between the core machinery of autophagy and mitosis but also illustrate the positive function of ULK1-ATG13 and their phosphorylation by CDK1 in mitotic autophagy regulation.

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Section: Ulk1/atg13 Phosphorylation By Mtor Ampk and Cdk1mentioning

confidence: 99%

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

Tian

et al. 2020

PLoS Biol

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“…Two papers (one by Li and colleagues in this issue and another recently published in Molecular Cell by Odle and colleagues) reveal that CDK1 phosphorylates the autophagy machinery [26,27] (Fig 1). In these works, both groups observe up-shifted bands of ULK1 and ATG13 in mitotic cell lysates.…”

Section: Phosphorylation Of the Atg Proteins During Mitosismentioning

confidence: 94%

Mitotic phosphorylation of the ULK complex regulates cell cycle progression

2020

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Autophagy is an intracellular degradation pathway targeting organelles and macromolecules, thereby regulating various cellular functions. Phosphorylation is a key posttranscriptional protein modification implicated in the regulation of biological function including autophagy. Under asynchronous conditions, autophagy activity is predominantly suppressed by mechanistic target of rapamycin (mTOR) kinase, but whether autophagy-related genes (ATG) proteins are phosphorylated differentially throughout the sequential phases of the cell cycle remains unclear. In this issue, Li and colleagues report that cyclin-dependent kinase 1 (CDK1) phosphorylates the ULK complex during mitosis. This phosphorylation induces autophagy and, surprisingly, is shown to drive cell cycle progression. This work reveals a yet-unappreciated role for autophagy in cell cycle progression and enhances our understanding of the specific phase-dependent autophagy regulation during cellular growth and proliferation.

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“…These Golgi-derived autophagosomes promote clearance of cytosolic DNA and incoming DNA viruses like HSV1 [80]. Although mitotic cells appear to avoid classical induction of autophagy via CDK1 phosphorylation of ATG13, ULK1, and ATG14 [81,82], downstream STING-dependent activation of autophagophore formation/elongation via WIPI2/ATG5 during open mitosis could be deleterious to daughter cell survival [83,84].…”

Section: Cgas and Sting Are Non-responsive During Mitosismentioning

confidence: 99%

Attenuation of cGAS/STING Activity During Mitosis

Uhlorn

Gamez

et al. 2019

Preprint

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The innate immune system recognizes cytosolic DNA associated with microbial infections or cellular stress via the cGAS/STING pathway, leading to activation of phospho-IRF3 and downstream IFN-I and senescence responses. To prevent hyperactivation, cGAS/STING is presumed to be non-responsive to chromosomal self DNA during open mitosis, though specific regulatory mechanisms are lacking. Given a role for the Golgi in STING activation, we investigated the state of the cGAS/STING pathway in interphase cells with artificially vesiculated Golgi and in cells arrested in mitosis. We find that while cGAS activity is impaired through interaction with mitotic chromosomes, Golgi integrity has little effect on the enzyme's production of cGAMP. In contrast, STING activation in response to either foreign DNA (cGAS-dependent) or exogenous cGAMP is impaired by a vesiculated Golgi. Overall our data suggest a secondary means for cells to limit potentially harmful cGAS/STING responses during open mitosis via natural Golgi vesiculation.

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

Abstract: Highlights d Autophagy initiation is repressed during mitosis, even during nutrient deprivation d RAPTOR phosphorylation in mitosis prevents mTORC1 localization to lysosomes d mTORC1 is inhibited during mitosis d CDK1 phosphorylates autophagy regulators at mTORC1 sites to repress autophagy

Cited by 89 publications

References 76 publications

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

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

Mitotic phosphorylation of the ULK complex regulates cell cycle progression

Attenuation of cGAS/STING Activity During Mitosis

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