Autocleavage of separase suppresses its premature activation by promoting binding to cyclin B1
Autocleavage of separase suppresses its premature activation by promoting binding to cyclin B1
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DOI：
10.1016/j.celrep.2022.111723
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发表时间：
2022-11-29
期刊：
影响因子：
8.8
通讯作者：
Hirota，Toru
中科院分区：
文献类型：
--
作者：
Shindo，Norihisa;Kumada，Kazuki;Hirota，Toru
准确的染色体分离需要分离酶的及时激活，分离酶是一种在中期到后期转变过程中裂解黏结蛋白的蛋白酶。然而，在此事件发生之前保持分离酶不活跃的机制尚不清楚。我们提供的证据表明，分离酶自裂解在这一过程中起重要作用。我们发现分离酶自裂的抑制导致在后期开始之前过早的活性，伴随着染色体桥的形成和纺锤体摇摆。这种解除管制归因于细胞周期蛋白B1与分离酶的结合减少，这种结合发生在中期到后期转变期间。此外，当分离酶发生突变，使细胞周期蛋白B1的调控变得无关紧要，从而使分离酶保持在安全蛋白结合的形式，由自裂抑制诱导的解除管制被挽救。我们的研究结果揭示了分离酶自裂在调节分离酶中的生理作用，这确保了染色体的忠实分离。
Accurate chromosome segregation requires timely activation of separase, a protease that cleaves cohesin during the metaphase-to-anaphase transition. However, the mechanism that maintains the inactivity of separase prior to this event remains unclear. We provide evidence that separase autocleavage plays an essential role in this process. We show that the inhibition of separase autocleavage results in premature activity before the onset of anaphase, accompanied by the formation of chromosomal bridges and spindle rocking. This deregulation is attributed to the reduced binding of cyclin B1 to separase that occurs during the metaphase-to-anaphase transition. Furthermore, when separase is mutated to render the regulation by cyclin B1 irrelevant, which keeps separase in securin-binding form, the deregulation induced by autocleavage inhibition is rescued. Our results reveal a physiological role of separase autocleavage in regulating separase, which ensures faithful chromosome segregation.