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Separase-triggered apoptosis enforces minimal length of mitosis
Nature ( IF 50.5 ) Pub Date : 2020-04-08 , DOI: 10.1038/s41586-020-2187-y
Susanne Hellmuth 1 , Olaf Stemmann 1
Affiliation  

Prolonged mitosis often results in apoptosis1. Shortened mitosis causes tumorigenic aneuploidy, but it is unclear whether it also activates the apoptotic machinery2. Separase, a cysteine protease and trigger of all eukaryotic anaphases, has a caspase-like catalytic domain but has not previously been associated with cell death3,4. Here we show that human cells that enter mitosis with already active separase rapidly undergo death in mitosis owing to direct cleavage of anti-apoptotic MCL1 and BCL-XL by separase. Cleavage not only prevents MCL1 and BCL-XL from sequestering pro-apoptotic BAK, but also converts them into active promoters of death in mitosis. Our data strongly suggest that the deadliest cleavage fragment, the C-terminal half of MCL1, forms BAK/BAX-like pores in the mitochondrial outer membrane. MCL1 and BCL-XL are turned into separase substrates only upon phosphorylation by NEK2A. Early mitotic degradation of this kinase is therefore crucial for preventing apoptosis upon scheduled activation of separase in metaphase. Speeding up mitosis by abrogation of the spindle assembly checkpoint results in a temporal overlap of the enzymatic activities of NEK2A and separase and consequently in cell death. We propose that NEK2A and separase jointly check on spindle assembly checkpoint integrity and eliminate cells that are prone to chromosome missegregation owing to accelerated progression through early mitosis.



中文翻译:

分离酶触发的细胞凋亡强制有丝分裂的最小长度

有丝分裂延长通常会导致细胞凋亡1。有丝分裂缩短会导致致瘤性非整倍体,但尚不清楚它是否也激活了凋亡机制2。分离酶是一种半胱氨酸蛋白酶,是所有真核生物后期的触发剂,具有类似半胱天冬酶的催化结构域,但之前并未与细胞死亡相关3,4. 在这里,我们表明,由于分离酶直接切割抗凋亡 MCL1 和 BCL-XL,进入有丝分裂时已经具有活性的分离酶的人类细胞在有丝分裂中迅速死亡。切割不仅可以防止 MCL1 和 BCL-XL 隔离促凋亡 BAK,而且还可以将它们转化为有丝分裂中死亡的活性促进剂。我们的数据强烈表明,最致命的切割片段,即 MCL1 的 C 端半部分,在线粒体外膜中形成 BAK/BAX 样孔。MCL1 和 BCL-XL 仅在被 NEK2A 磷酸化后才转化为分离酶底物。因此,这种激酶的早期有丝分裂降解对于在中期计划激活分离酶后防止细胞凋亡至关重要。通过取消纺锤体组装检查点来加速有丝分裂会导致 NEK2A 和分离酶的酶活性在时间上重叠,从而导致细胞死亡。我们建议 NEK2A 和分离酶联合检查纺锤体装配检查点的完整性,并消除由于早期有丝分裂加速进展而容易发生染色体错误分离的细胞。

更新日期:2020-04-08
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