Objective: Depletion of islet β cells plays a crucial role in the onset of diabetes mellitus. Cell autophagy, as a self-healing process, contributes to maintaining metabolic homeostasis and can protect islet β cells from apoptosis upon starvation or high glucose stress. However, the underlying regulatory network of the autophagic process in islet β cells has not been fully explored.
Materials and methods: Murine β-TC3 cells treated with different concentrations of glucose, and wild-type or the Ser484 mutant human cell division cycle gene 14A (hCDC14A) was transfected. Cell viability, proliferation and autophagy as well as islet secretion were studied. The mTOR and AMPK signaling pathways were investigated by western blots. Zipper-interacting protein kinase was studied using mass spectrometry and immunoprecipitation.
Results: Overexpression of wild-type hCDC14A, but not the Ser484 mutant hCDC14A, promoted cell viability, proliferation and autophagy accompanied by enhanced islet secretion and reduced cell apoptosis via mTOR pathway inhibition as well AMPK pathway activation in β-TC3 cells and vice versa. Furthermore, Zipper-interacting protein kinase (ZIPK), also known as DAPK3, was found to interact with hCDC14A primarily for Ser484 phosphorylation, and ZIPK knockdown could affect the phosphorylation of hCDC14A and weaken cell death or cell cycle modulation.
Conclusions: Taken together, our results may provide new insight into the role of hCDC14A in the autophagy of islet β cells and suggest the potential therapeutic value of hCDC14A phosphorylation in the prevention and treatment of diabetes.