小柯机器人

德国科隆大学Hamid Kashkar课题组研究发现Caspase-8是细胞凋亡、坏死和细胞焦亡的分子开关。相关论文2019年11月20日在线发表在《自然》上。

研究表明，酶活性丧失的CASP8（C362S）的表达，通过诱导细胞坏死性凋亡和细胞焦亡引起小鼠胚胎致死。与Casp8^-/-小鼠类似，在内皮细胞坏死性凋亡导致心血管缺陷后Casp8^{C362S / C362S}小鼠胚胎死亡。MLKL缺陷回复了心血管表型，但却引起了Casp8^{C362S / C362S}小鼠的围产期死亡，表明CASP8（C362S）在胚胎发育的后期导致细胞坏死性凋亡非依赖性死亡。与肠上皮细胞特异性Casp8敲除小鼠相似，肠上皮细胞中caspase-8催化活性的特异性丧失引起肠道炎症。通过额外敲除Mlk1来抑制细胞坏死性凋亡会严重加剧肠道炎症，并在Mlkl敲除小鼠中导致早产致死，这是由于肠上皮细胞中的caspase-8催化活性特异性丧失。CASP8（C362S）的表达引发了ASC斑点的形成，caspase-1的活化和IL-1β的分泌。在Casp8^{C362S / C362S}Mlk1^-/-Asc^-/-或Casp8^C362S/C362SMlkl^-/-Casp1^-/-小鼠中，胚胎致死率和早产死亡率都得到了完全回复，这表明当细胞坏死性凋亡被阻断，炎性小体的激活促进CASP8(c362)介导的组织病理学。因此，caspase-8代表了控制细胞坏死性凋亡和细胞焦亡的分子开关，并阻止了胚胎发育和成年期的组织损伤。

据了解，Caspase-8是外部细胞坏死性凋亡的起始半胱天冬酶，并抑制由RIPK3和MLKL介导的细胞坏死。因此，小鼠中caspase-8缺失会引起胚胎致死性，可通过Ripk3或Mlkl的敲除来回复其表型。

附：英文原文

Title: Caspase-8 is the molecular switch for apoptosis, necroptosis and pyroptosis

Author: Melanie Fritsch, Saskia D. Gnther, Robin Schwarzer, Marie-Christine Albert, Fabian Schorn, J. Paul Werthenbach, Lars M. Schiffmann, Neil Stair, Hannah Stocks, Jens M. Seeger, Mohamed Lamkanfi, Martin Krnke, Manolis Pasparakis, Hamid Kashkar

Issue&Volume: 2019-11-20

Abstract: Caspase-8 is the initiator caspase of extrinsic apoptosis and inhibits necroptosis mediated by RIPK3 and MLKL. Accordingly, caspase-8 deficiency in mice causes embryonic lethality3, which can be rescued by deletion of either Ripk3 or Mlkl46. Here we show that the expression of enzymatically inactive CASP8(C362S) causes embryonic lethality in mice by inducing necroptosis and pyroptosis. Similar to Casp8^-/- mice Casp8^C362S/C362S mouse embryos died after endothelial cell necroptosis leading to cardiovascular defects. MLKL deficiency rescued the cardiovascular phenotype but unexpectedly caused perinatal lethality in Casp8^C362S/C362S mice, indicating that CASP8(C362S) causes necroptosis-independent death at later stages of embryonic development. Specific loss of the catalytic activity of caspase-8 in intestinal epithelial cells induced intestinal inflammation similar to intestinal epithelial cell-specific Casp8 knockout mice. Inhibition of necroptosis by additional deletion of Mlkl severely aggravated intestinal inflammation and caused premature lethality in Mlkl knockout mice with specific loss of caspase-8 catalytic activity in intestinal epithelial cells. Expression of CASP8(C362S) triggered the formation of ASC specks, activation of caspase-1 and secretion of IL-1. Both embryonic lethality and premature death were completely rescued in Casp8^C362S/C362SMlkl^-/-Asc^-/- or Casp8^C362S/C362SMlkl^-/-Casp1^-/- mice, indicating that the activation of the inflammasome promotes CASP8(C362S)-mediated tissue pathology when necroptosis is blocked. Therefore, caspase-8 represents the molecular switch that controls apoptosis, necroptosis and pyroptosis, and prevents tissue damage during embryonic development and adulthood. The enzymatic activity of caspase-8 controls apoptosis, necroptosis and pyroptosis, and prevents tissue damage during embryonic development and adulthood in mice.

DOI: 10.1038/s41586-019-1770-6

Source:https://www.nature.com/articles/s41586-019-1770-6

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