Caspase-8 is the molecular switch for apoptosis, necroptosis and pyroptosis
Caspase-8 is the molecular switch for apoptosis, necroptosis and pyroptosis
复制标题
DOI：
10.1038/s41586-019-1770-6
复制
发表时间：
2019-11-28
期刊：
影响因子：
64.8
通讯作者：
Kashkar, Hamid
中科院分区：
文献类型：
--
作者：
Fritsch, Melanie;Gunther, Saskia D.;Kashkar, Hamid
半胱天冬酶-8是外源性凋亡的起始半胱天冬酶（1，2），并抑制RIPK 3和MLKL介导的坏死性凋亡。因此，小鼠中的半胱天冬酶-8缺陷导致胚胎致死（3），这可以通过缺失Ripk 3或Mlkl来挽救（4-6）。在这里，我们表明，表达的酶失活CASP 8（C362 S）导致胚胎死亡的小鼠通过诱导坏死性凋亡和pyroptosis。与Casp 8（-/-）小鼠相似（3，7），Casp 8（C362 S/C362 S）小鼠胚胎在内皮细胞坏死性凋亡后死亡，导致心血管缺陷。MLKL缺陷挽救了心血管表型，但意外地导致了Casp 8（C362 S/C362 S）小鼠的围产期死亡，表明CASP 8（C362 S）在胚胎发育的后期阶段引起坏死性凋亡非依赖性死亡。肠上皮细胞中caspase-8催化活性的特异性丧失诱导了与肠上皮细胞特异性Casp 8敲除小鼠相似的肠道炎症（8）。通过额外缺失Mlkl抑制坏死性凋亡严重加重了肠道炎症，并导致Mlkl敲除小鼠过早死亡，肠上皮细胞中半胱天冬酶-8催化活性特异性丧失。CASP 8（C362 S）的表达触发ASC斑点的形成、caspase-1的活化和IL-1 β的分泌。在Casp 8（C362 S/C362 S）Mlkl（-/-）Asc（-/-）或Casp 8（C362 S/C362 S）Mlkl（-/-）Caspl（-/-）小鼠中完全挽救了胚胎致死和过早死亡，表明当坏死性凋亡被阻断时，炎性小体的激活促进了CASP 8（C362 S）介导的组织病理学。因此，caspase-8代表了控制细胞凋亡、坏死性凋亡和焦亡的分子开关，并防止胚胎发育和成年期间的组织损伤。
Caspase-8 is the initiator caspase of extrinsic apoptosis(1,2) and inhibits necroptosis mediated by RIPK3 and MLKL. Accordingly, caspase-8 deficiency in mice causes embryonic lethality(3), which can be rescued by deletion of either Ripk3 or Mlkl(4-6). 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(3,7), 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(8). 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 beta. Both embryonic lethality and premature death were completely rescued in Casp8(C362S/C362S)Mlkl(-/-)Asc(-/-) or Casp8(C362S/C362S)Mlkl(-/-)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.