RIPK1 and Caspase-8 Ensure Chromosome Stability Independently of Their Role in Cell Death and Inflammation
RIPK1 and Caspase-8 Ensure Chromosome Stability Independently of Their Role in Cell Death and Inflammation
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DOI：
10.1016/j.molcel.2018.11.010
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发表时间：
2019-02-07
期刊：
影响因子：
16
通讯作者：
Meier, Pascal
中科院分区：
文献类型：
--
作者：
Liccardi, Gianmaria;Garcia, Laura Ramos;Meier, Pascal
受体相互作用蛋白激酶（RIPK）1通过形成半胱天冬酶-8活化核糖体复合物，正性和负性调节细胞凋亡、坏死性凋亡和炎症，作为组织稳态的关键介质发挥作用。在这里，我们报告了一个意想不到的细胞死亡和炎症独立的功能RIPK 1和Caspase-8，促进有丝分裂中的忠实染色体排列，从而确保基因组的稳定性。我们发现，ripoptosome复合物逐渐形成细胞进入有丝分裂，中期达到高峰，细胞退出有丝分裂解体。Ripk 1或Caspase-8的遗传缺失和有丝分裂特异性抑制导致独立于MLKL的染色体排列缺陷。我们发现Polo样激酶1（PLK 1）被募集到有丝分裂的核糖体中，其中PLK 1的活性通过RIPK 1依赖性募集和Caspase-8介导的切割来控制。核糖体组装的精细平衡是必需的，因为去调节的核糖体活性调节下游效应物（如BUBR 1）的PLK 1依赖性磷酸化。我们的数据表明，ripoptosome介导的PLK 1的调节有助于忠实的染色体分离在有丝分裂。
Receptor-interacting protein kinase (RIPK) 1 functions as a key mediator of tissue homeostasis via formation of Caspase-8 activating ripoptosome complexes, positively and negatively regulating apoptosis, necroptosis, and inflammation. Here, we report an unanticipated cell-death-and inflammation- independent function of RIPK1 and Caspase-8, promoting faithful chromosome alignment in mitosis and thereby ensuring genome stability. We find that ripoptosome complexes progressively form as cells enter mitosis, peaking at metaphase and disassembling as cells exit mitosis. Genetic deletion and mitosis-specific inhibition of Ripk1 or Caspase-8 results in chromosome alignment defects independently of MLKL. We found that Polo-like kinase 1 (PLK1) is recruited into mitotic ripoptosomes, where PLK1's activity is controlled via RIPK1-dependent recruitment and Caspase-8-mediated cleavage. A fine balance of ripoptosome assembly is required as deregulated ripoptosome activity modulates PLK1-dependent phosphorylation of downstream effectors, such as BUBR1. Our data suggest that ripoptosome-mediated regulation of PLK1 contributes to faithful chromosome segregation during mitosis.