Department of Biochemistry, University of Oxford, Oxford, UK.
The Wellcome Centre for Cell Biology, Institute of Cell Biology, School of Biological Sciences, University of Edinburgh, Edinburgh, UK.
J Cell Biol. 2024 Nov 4;223(11). doi: 10.1083/jcb.202401169. Epub 2024 Aug 28.
Kinetochores form the interface between chromosomes and spindle microtubules and are thus under tight control by a complex regulatory circuitry. The Aurora B kinase plays a central role within this circuitry by destabilizing improper kinetochore-microtubule attachments and relaying the attachment status to the spindle assembly checkpoint. Intriguingly, Aurora B is conserved even in kinetoplastids, a group of early-branching eukaryotes which possess a unique set of kinetochore proteins. It remains unclear how their kinetochores are regulated to ensure faithful chromosome segregation. Here, we show in Trypanosoma brucei that Aurora B activity controls the metaphase-to-anaphase transition through phosphorylation of the divergent Bub1-like protein KKT14. Depletion of KKT14 overrides the metaphase arrest resulting from Aurora B inhibition, while expression of non-phosphorylatable KKT14 delays anaphase onset. Finally, we demonstrate that re-targeting Aurora B to the outer kinetochore suffices to promote mitotic exit but causes extensive chromosome missegregation in anaphase. Our results indicate that Aurora B and KKT14 are involved in an unconventional circuitry controlling cell cycle progression in trypanosomes.
动粒作为染色体与纺锤体微管的连接界面,受到一个复杂的调控网络的严格控制。Aurora B 激酶在这个调控网络中起着核心作用,它通过破坏不正确的动粒-微管连接,并将连接状态传递给纺锤体组装检查点,从而发挥作用。有趣的是,Aurora B 在动基体生物中也被保守,动基体生物是一组早期分支的真核生物,它们拥有一套独特的动粒蛋白。目前尚不清楚它们的动粒是如何被调控以确保染色体的正确分离。在这里,我们在布氏锥虫中表明,Aurora B 的活性通过磷酸化差异表达的 Bub1 样蛋白 KKT14 来控制从中期到后期的转变。KKT14 的缺失会忽略由于 Aurora B 抑制而导致的中期停滞,而表达不可磷酸化的 KKT14 则会延迟后期的开始。最后,我们证明将 Aurora B 重新靶向到外动粒足以促进有丝分裂退出,但在后期会导致广泛的染色体错误分离。我们的研究结果表明,Aurora B 和 KKT14 参与了一个控制锥虫细胞周期进程的非常规调控网络。