CDK1 phosphorylates ULK1-ATG13 complex to regulate mitotic autophagy and Taxol chemosensitivity

Abstract

ULK1-ATG13 is the most upstream autophagy initiation complex that is phosphorylated by mTORC1 and AMPK to induce autophagy in asynchronous conditions. However, the phospho-regulation and function of ULK1-ATG13 in mitosis and cell cycle remains unknown. Here we show that ULK1-ATG13 complex is differentially regulated throughout the cell cycle. Notably, in mitosis, both ULK1 and ATG13 are highly phosphorylated by CDK1/cyclin B, the key cell cycle machinery. Combining mass spectrometry and site-directed mutagenesis, we found that CDK1-induced ULK1-ATG13 phosphorylation positively regulates mitotic autophagy and Taxol chemosensitivity, and some phosphorylation sites occur in cancer patients. Moreover, double knockout 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 machineries of autophagy and mitosis, illustrate the mitotic autophagy regulation mechanism, but also provide ULK1-ATG13 as potential targets for cancer therapy.