Abstract
Unc-51-like autophagy activating kinase 1 (ULK1)-autophagy-related 13 (ATG13) is the most upstream autophagy initiation complex that is phosphorylated by mammalian target-of-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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies / metabolism
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Autophagy*
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Autophagy-Related Protein-1 Homolog / metabolism*
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Autophagy-Related Proteins / metabolism*
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CDC2 Protein Kinase / metabolism*
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Cell Line
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Cyclin B / metabolism
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Female
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Humans
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Intracellular Signaling Peptides and Proteins / metabolism*
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Mice, Inbred BALB C
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Mice, Nude
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Mitosis*
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Phosphorylation
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Substrate Specificity
Substances
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ATG13 protein, human
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Antibodies
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Autophagy-Related Proteins
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Cyclin B
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Intracellular Signaling Peptides and Proteins
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Autophagy-Related Protein-1 Homolog
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ULK1 protein, human
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CDC2 Protein Kinase
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CDK1 protein, human
Grants and funding
This work was supported by the National Key Research and Development Program of China (#2016YFA0400900), Major/Innovative Program of Development Foundation of Hefei Center for Physical Science and Technology (2016FXCX004), Key Program of 13th five-year plan, CASHIPS (KP-2017-26) and CASHIPS Director’s Fund (YZJJ201704) to XZ, National Natural Science Foundation of China (31900508), CASHIPS Director’s Fund (YZJJ2019QN17) and Anhui Natural Science Foundation (1908085MC88) to ZL. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.