Plk1 regulates mutant IDH1 enzyme activity and mutant IDH2 ubiquitination in mitosis

Abstract

Mutations in the metabolic enzymes, IDH1 and IDH2 are frequently found in glioma, chondrosarcoma, and acute myeloid leukemia. In our previous study, we showed that mutant IDH1 and IDH2 proteins levels are high in mitosis, and mutant IDH1 enzyme activity increases in mitosis. In another study, we observed that mutant IDH2 is ubiquitinated in mitosis in an APC/C-dependent manner. To orchestrate mitosis, kinases phosphorylate key proteins and regulate their functions. But it is unknown, whether mitotic kinases regulate mutant IDH1 and IDH2. As IDH1 and IDH2 have 66% sequence identity, thus we hypothesized that a common mitotic kinase(s) may regulate mutant IDH1 and IDH2 in mitosis. To test our hypothesis, we examined mutant IDH1 and IDH2 binding to mitotic kinases and determined their role in regulating mutant IDH1 and IDH2 in mitosis. Here, we observed that Cdk1/Cyclin B1 phosphorylated mutant IDH1 and IDH2 binds Plk1. Conserved Plk1 phosphobinding sites in IDH1 and IDH2 are important for Plk1 binding. We found that Plk1 regulates mutant IDH1 enzyme activity and blocking Plk1 decreases D-2HG, whereas, overexpressing Plk1 increases D-2HG levels. Furthermore, blocking Plk1 decreases mutant IDH2 ubiquitination, whereas, overexpressing Plk1 increases mutant IDH2 ubiquitination in mitosis. We conclude that Plk1 regulates mutant IDH1 enzyme activity and mutant IDH2 ubiquitination in mitosis. Based on our results, we suggest that Plk1 can be a therapeutic target in mutant IDH-linked tumours.

Keywords: Cdk1/cyclin B1; D-2HG; Mutant IDH1; Mutant IDH2; Plk1; Ubiquitination.