Laboratory of Pathophysiological Cell Signaling, Department of Biology, Faculty of Science and Bioengineering Sciences, Vrije Universiteit Brussel, Pleinlaan 2, 1050, Brussels, Belgium.
Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1PD, UK.
Oncogene. 2020 Sep;39(37):6009-6023. doi: 10.1038/s41388-020-01396-8. Epub 2020 Aug 8.
Aurora B kinase plays essential roles in mitosis. Its protein levels increase before the onset of mitosis and sharply decrease during mitosis exit. The latter decrease is due to a balance between the actions of the E3 ubiquitin ligase anaphase-promoting complex or cyclosome (activated by the Cdh1 adapter), and the deubiquitinating enzyme USP35. Aurora B also executes important functions in interphase. Abnormal modulation of Aurora B in interphase leads to cell cycle defects often linked to aberrant chromosomal condensation and segregation. Very little is however known about how Aurora B levels are regulated in interphase. Here we found that USP13-associates with and stabilizes Aurora B in cells, especially before their entry into mitosis. In order for USP13 to exert its stabilizing effect on Aurora B, their association is promoted by the Aurora B-mediated phosphorylation of USP13 at Serine 114. We also present evidence that USP13 instigates Aurora B deubiquitination and/or protect it from degradation in a non-catalytic manner. In addition, we report that genetic or chemical modulation of the cellular levels/activity of USP13 affects unperturbed cell-cycle progression. Overall our study unveils the molecular and cellular connections of the USP13-Aurora B axis, which potentially participates in the rewiring of the cell cycle happening in cancer cells.
极光激酶 B 在有丝分裂中起着至关重要的作用。其蛋白水平在有丝分裂开始前升高，在有丝分裂退出时急剧下降。后者的减少是由于 E3 泛素连接酶后期促进复合物或周期蛋白（由 Cdh1 衔接子激活）和去泛素化酶 USP35 的作用之间的平衡。极光激酶 B 在间期也执行重要功能。间期极光激酶 B 的异常调节导致细胞周期缺陷，通常与异常的染色体凝聚和分离有关。然而，关于极光激酶 B 在间期的水平如何调节，人们知之甚少。在这里，我们发现 USP13 与 Aurora B 在细胞中结合并稳定 Aurora B，尤其是在它们进入有丝分裂之前。为了使 USP13 对 Aurora B 发挥稳定作用，它们的结合通过 Aurora B 介导的 USP13 丝氨酸 114 磷酸化来促进。我们还提供了证据表明，USP13 以非催化方式引发 Aurora B 的去泛素化和/或保护它免受降解。此外，我们报告说，USP13 的细胞水平/活性的遗传或化学调节会影响未受干扰的细胞周期进程。总的来说，我们的研究揭示了 USP13-Aurora B 轴的分子和细胞连接，该轴可能参与了癌细胞中发生的细胞周期重排。
