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Caspase-8决定细胞死亡的不同方式
2019-11-14 14:39

美国基因泰克公司Vishva M. Dixit和Kim Newton研究团队发现caspase-8的活性决定了细胞死亡途径之间的可塑性。 该项研究成果11月13日在线发表在《自然》上。

研究人员发现突变的CASP8(C362A)诱导形成ASC(也称为PYCARD)斑点样蛋白,并且在胚胎期18天左右,MLKL缺陷小鼠肠道中会发生caspase-1介导的GSDMD以及caspase 3和7的切割。

由于许多Casp8C362A / C362AMlkl-/-Casp1-/-和Casp8C362A / C362AMlkl-/-Asc-/-小鼠在断奶后仍可存活,因此Caspase-1以及其连接蛋白ASC导致了小鼠围产期致死的表型。转染研究表明,无活性的caspase-8与有活性的caspase-8具有不同的构象,从而使其前结构域与ASC结合。Casp8C362A / C362AMlkl-/-和Casp8C362A / C362AMlkl-/-Casp1-/-小鼠肠道中脂多糖传感器caspase-11的上调也导致了致死性,因为Casp8C362A / C362AMlkl-/-Casp1-/-Casp11-/-(Casp11也称为Casp4)新生小鼠比Casp8C362A / C362AMlkl-/-Casp1-/-新生小鼠存活率更高。最后,Casp8C362A / C362ARipk3-/-Casp1-/-Casp11-/-小鼠比Casp8C362A / C362AMlkl-/-Casp1-/-Casp11-/-小鼠存活时间更长,这表明RIPK3的非坏死性功能也有助于细胞死亡。因此,当caspase-8依赖的细胞凋亡和MLKL依赖的坏死被抑制时,死亡途径中的未知可塑性被揭示。

据介绍,Caspase-8是一种具有促死亡和促生存功能的蛋白酶:它可以介导TNFR11类死亡受体诱导的细胞凋亡,也可以抑制由RIPK3激酶和假激酶MLKL介导的细胞坏死。缺乏caspase-8的小鼠表现出MLKL依赖的胚胎致死性,与表达无催化作用的CASP8(C362A)的小鼠一样。 Casp8C362A / C362AMlkl-/-小鼠在围生期死亡,而Casp8-/-Mlkl-/-小鼠则可以存活,这表明无活性的caspase-8也具有促死亡的辅助功能。

附:英文原文

Title: Activity of caspase-8 determines plasticity between cell death pathways

Author: Kim Newton, Katherine E. Wickliffe, Allie Maltzman, Debra L. Dugger, Rohit Reja, Yue Zhang, Merone Roose-Girma, Zora Modrusan, Meredith S. Sagolla, Joshua D. Webster, Vishva M. Dixit

Issue&Volume: 2019-11-13

Abstract: Caspase-8 is a protease with both pro-death and pro-survival functions: it mediates apoptosis induced by death receptors such as TNFR11, and suppresses necroptosis mediated by the kinase RIPK3 and the pseudokinase MLKL24. Mice that lack caspase-8 display MLKL-dependent embryonic lethality4, as do mice that express catalytically inactive CASP8(C362A)5. Casp8C362A/C362AMlkl/ mice die during the perinatal period5, whereas Casp8/Mlkl/ mice are viable4, which indicates that inactive caspase-8 also has a pro-death scaffolding function. Here we show that mutant CASP8(C362A) induces the formation of ASC (also known as PYCARD) specks, and caspase-1-dependent cleavage of GSDMD and caspases 3 and 7 in MLKL-deficient mouse intestines around embryonic day 18. Caspase-1 and its adaptor ASC contributed to the perinatal lethal phenotype because a number of Casp8C362A/C362AMlkl/Casp1/ and Casp8C362A/C362AMlkl/Asc/ mice survived beyond weaning. Transfection studies suggest that inactive caspase-8 adopts a distinct conformation to active caspase-8, enabling its prodomain to engage ASC. Upregulation of the lipopolysaccharide sensor caspase-11 in the intestines of both Casp8C362A/C362AMlkl/ and Casp8C362A/C362AMlkl/Casp1/ mice also contributed to lethality because Casp8C362A/C362AMlkl/Casp1/Casp11/ (Casp11 is also known as Casp4) neonates survived more often than Casp8C362A/C362AMlkl/Casp1/ neonates. Finally, Casp8C362A/C362ARipk3/Casp1/Casp11/ mice survived longer than Casp8C362A/C362AMlkl/Casp1/Casp11/ mice, indicating that a necroptosis-independent function of RIPK3 also contributes to lethality. Thus, unanticipated plasticity in death pathways is revealed when caspase-8-dependent apoptosis and MLKL-dependent necroptosis are inhibited. Alternative cell death pathways are revealed in the absence of caspase-8-dependent apoptosis and MLKL-dependent necroptosis.

DOI: 10.1038/s41586-019-1752-8

Source: https://www.nature.com/articles/s41586-019-1752-8

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
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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