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分离酶通过诱导细胞凋亡限制有丝分裂的最短周期
2020-04-09 12:47

2020年4月8日出版的《自然》杂志在线发表了德国拜罗伊特大学Olaf Stemmann课题组的最新成果。经过不懈努力,他们发现分离酶通过诱导细胞凋亡从而限制有丝分裂的最短周期。

在本研究中,研究人员发现在进入有丝分裂前就已具有分离酶活性的人体细胞在进入有丝分裂后会迅速死亡,这是由于分离酶直接切割抗凋亡蛋白MCL1和BCL-XL造成的。分离酶切割不仅阻止MCL1和BCL-XL从促凋亡蛋白BAK中隔离,而且在有丝分裂过程中将它们转化为死亡的活跃启动子。该数据表明,最致命的裂解片段(MCL1 C末端的一半)在线粒体外膜中形成BAK / BAX样的孔。MCL1和BCL-XL仅在被NEK2A磷酸化后才能成分离酶的底物。

因此,在有丝分裂早期该激酶的降解对于预防中期分离酶激活后的凋亡至关重要。通过纺锤体装配检查点的缺失来加速有丝分裂周期会导致NEK2A和分离酶的酶活性在时间上重叠,从而导致细胞死亡。研究人员猜想NEK2A和分离酶共同调控纺锤体装配检查点的完整性,并清除由于早期有丝分裂加速而易于发生染色体错位的细胞。

据悉,有丝分裂周期延长通常会导致细胞凋亡。缩短有丝分裂周期会导致致瘤性染色体非整倍性,但尚不清楚其是否还会激活细胞凋亡。分离酶是一种半胱氨酸蛋白酶,是所有真核生物有丝分裂后期的触发物,具有类似caspase的催化结构域,但之前未将其与细胞死亡相关联。

附:英文原文

Title: Separase-triggered apoptosis enforces minimal length of mitosis

Author: Susanne Hellmuth, Olaf Stemmann

Issue&Volume: 2020-04-08

Abstract: 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.

DOI: 10.1038/s41586-020-2187-y

Source: https://www.nature.com/articles/s41586-020-2187-y

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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