CDK11^p58 Is Required for Centriole Duplication and Plk4 Recruitment to Mitotic Centrosomes

BackgroundCDK11p58 is a mitotic protein kinase, which has been shown to be required for different mitotic events such as centrosome maturation, chromatid cohesion and cytokinesis. Methodology/Principal FindingsIn addition to these previously described roles, our study shows that CDK11p58 inhibition induces a failure in the centriole duplication process in different human cell lines. We propose that this effect is mediated by the defective centrosomal recruitment of proteins at the onset of mitosis. Indeed, Plk4 protein kinase and the centrosomal protein Cep192, which are key components of the centriole duplication machinery, showed reduced levels at centrosomes of mitotic CDK11-depleted cells. CDK11p58, which accumulates only in the vicinity of mitotic centrosomes, directly interacts with the centriole-associated protein kinase Plk4 that regulates centriole number in cells. In addition, we show that centriole from CDK11 defective cells are not able to be over duplicated following Plk4 overexpression. Conclusion/SignificanceWe thus propose that CDK11 is required for centriole duplication by two non-mutually-exclusive mechanisms. On one hand, the observed duplication defect could be caused indirectly by a failure of the centrosome to fully maturate during mitosis. On the other hand, CDK11p58 could also directly regulate key centriole components such as Plk4 during mitosis to trigger essential mitotic centriole modifications, required for centriole duplication during subsequent interphase.背景 CDK11p58是一种有丝分裂蛋白激酶，已被证实参与多种有丝分裂事件，例如中心体成熟、染色单体黏附及胞质分裂。 方法与主要发现 除上述已报道的功能外，本研究发现抑制CDK11p58会导致不同人类细胞系中的中心粒复制过程出现障碍。我们提出该效应是通过有丝分裂早期蛋白质的中心体招募缺陷所介导的。确实，作为中心粒复制机器的关键组分，Plk4蛋白激酶与中心体蛋白Cep192在CDK11敲减的有丝分裂细胞的中心体上的水平显著降低。仅在有丝分裂中心体附近富集的CDK11p58可与调控细胞内中心粒数量的中心粒相关蛋白激酶Plk4直接相互作用。此外，我们证实，CDK11功能缺陷细胞中的中心粒无法在Plk4过表达后发生过度复制。 结论与意义 据此我们提出，CDK11通过两种非互斥的机制参与中心粒复制调控：一方面，观察到的复制缺陷可能间接源于有丝分裂期间中心体无法完全成熟；另一方面，CDK11p58还可在有丝分裂过程中直接调控Plk4等关键中心粒组分，以触发必要的有丝分裂中心粒修饰，而该修饰是后续间期中心粒复制所必需的。