Caspase-8決定細胞死亡的不同方式

Caspase-8決定細胞死亡的不同方式

作者：

小柯機器人

發布時間：2019/11/14 14:39:03

美國基因泰克公司Vishva M. Dixit和Kim Newton研究團隊發現caspase-8的活性決定了細胞死亡途徑之間的可塑性。 該項研究成果11月13日在線發表在《自然》上。

研究人員發現突變的CASP8（C362A）誘導形成ASC（也稱為PYCARD）斑點樣蛋白，並且在胚胎期18天左右，MLKL缺陷小鼠腸道中會發生caspase-1介導的GSDMD以及caspase 3和7的切割。

由於許多Casp8^{C362A / C362A}Mlkl^-/-Casp1^-/-和Casp^{8C362A / C362A}Mlkl^-/-Asc^-/-小鼠在斷奶後仍可存活，因此Caspase-1以及其連接蛋白ASC導致了小鼠圍產期致死的表型。轉染研究表明，無活性的caspase-8與有活性的caspase-8具有不同的構象，從而使其前結構域與ASC結合。Casp8^{C362A / C362A}Mlkl^-/-和Casp8^{C362A / C362A}Mlkl^-/-Casp1^-/-小鼠腸道中脂多糖傳感器caspase-11的上調也導致了致死性，因為Casp8^{C362A / C362A}Mlkl^-/-Casp1^-/-Casp11^-/-（Casp11也稱為Casp4）新生小鼠比Casp8^{C362A / C362A}Mlkl^-/-Casp1^-/-新生小鼠存活率更高。最後，Casp8^{C362A / C362A}Ripk3^-/-Casp1^-/-Casp11^-/-小鼠比Casp8^{C362A / C362A}Mlkl^-/-Casp1^-/-Casp11^-/-小鼠存活時間更長，這表明RIPK3的非壞死性功能也有助於細胞死亡。因此，當caspase-8依賴的細胞凋亡和MLKL依賴的壞死被抑制時，死亡途徑中的未知可塑性被揭示。

據介紹，Caspase-8是一種具有促死亡和促生存功能的蛋白酶：它可以介導TNFR11類死亡受體誘導的細胞凋亡，也可以抑制由RIPK3激酶和假激酶MLKL介導的細胞壞死。缺乏caspase-8的小鼠表現出MLKL依賴的胚胎致死性，與表達無催化作用的CASP8（C362A）的小鼠一樣。 Casp8^{C362A / C362A}Mlkl^-/-小鼠在圍生期死亡，而Casp8^-/-Mlkl^-/-小鼠則可以存活，這表明無活性的caspase-8也具有促死亡的輔助功能。

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