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.
Highlights
Autophagy occurs at basal levels in most tissues to selectively eliminate unwanted cellular components and can be induced in response to various physiological and pathological conditions
Unc-51-like autophagy activating kinase 1 (ULK1)-autophagy-related 13 (ATG13) complex is mainly phosphorylated by AMP-activated protein kinase (AMPK) and mammalian targetof-rapamycin complex 1 (mTORC1) in asynchronous conditions [18,19,20,21], but little was known about its regulation in mitosis
We found that the master cell cycle kinase cyclin-dependent kinase 1 (CDK1) phosphorylates ULK1-ATG13 complex to regulate its function in autophagy and cell cycle
Summary
Autophagy occurs at basal levels in most tissues to selectively eliminate unwanted cellular components and can be induced in response to various physiological and pathological conditions. Conserved autophagy-related (ATG) proteins play essential roles in autophagy nucleation, elongation, autophagosome closure, and maturation [1,2,3]. Unc-51-like autophagy activating kinase 1 (ULK1)/ATG1, a mammalian serine/threonine protein kinase, plays a key role in autophagy initiation [1]. It forms a complex with ATG13 and FAK familyinteracting protein of 200 kDa (FIP200), which enhance ULK1 kinase activity and are vital for its localization and stability, mediating mammalian target-of-rapamycin (mTOR) signaling to autophagy [4,5,6]. Many ATG proteins have been proven to have vital physiological roles in other cellular processes in higher eukaryotes [2].
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