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Cleavage of RIPK1 by caspase-8 is crucial for limiting apoptosis and necroptosis

机译：caspase-8切割RIPK1对于限制细胞凋亡和坏死性病变至关重要

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The aspartate-specific cysteine protease caspase-8 suppresses necroptotic cell death mediated by RIPK3 and MLKL. Indeed, mice that lack caspase-8 die in a RIPK3- and MLKL-dependent manner during embryogenesis(1-3). In humans, caspase-8 deficiency is associated with immunodeficiency(4) or very early onset inflammatory bowel disease(5). The substrates that are cleaved by caspase-8 to prevent necroptosis in vivo have not been defined. Here we show that knock-in mice that express catalytically inactive caspase-8(C362A) die as embryos owing to MLKL-dependent necroptosis, similar to caspase-8-deficient mice. Thus, caspase-8 must cleave itself, other proteins or both to inhibit necroptosis. Mice that express caspase-8(D212A/D218A/D225A/D387A), which cannot cleave itself, were viable, as were mice that express c-FLIP or CYLD proteins that had been mutated to prevent cleavage by caspase-8. By contrast, mice that express RIPK1(D325A), in which the caspase-8 cleavage site Asp325 had been mutated, died midgestation. Embryonic lethality was prevented by inactivation of RIPK1, loss of TNFR1, or loss of both MLKL and the caspase-8 adaptor FADD, but not by loss of MLKL alone. Thus, RIPK1(D325A) appears to trigger cell death mediated by TNF, the kinase activity of RIPK1 and FADD-caspase-8. Accordingly, dying endothelial cells that contain cleaved caspase-3 were abnormally abundant in yolk sacs of Ripk1(D325A/D325A) embryos. Heterozygous Ripk1(D325A/+) cells and mice were viable, but were also more susceptible to TNF-induced cell death than were wild-type cells or mice. Our data show that Asp325 of RIPK1 is essential for limiting aberrant cell death in response to TNF, consistent with the idea that cleavage of RIPK1 by caspase-8 is a mechanism for dismantling death-inducing complexes.
机译：天冬氨酸特异性半胱氨酸蛋白酶caspase-8抑制由RIPK3和MLKL介导的坏死性细胞死亡。的确，缺乏caspase-8的小鼠在胚胎发生过程中以RIPK3-和MLKL依赖性方式死亡（1-3）。在人类中，caspase-8缺乏症与免疫缺陷（4）或非常早期的炎症性肠病（5）相关。由胱天蛋白酶8切割以防止体内坏死的底物尚未确定。在这里，我们显示了表达无催化作用的caspase-8（C362A）的敲入小鼠由于MLKL依赖性坏死病而死为胚胎，类似于caspase-8缺陷小鼠。因此，caspase-8必须裂解自身，其他蛋白质或同时裂解两者才能抑制坏死性坏死。表达caspase-8（D212A / D218A / D225A / D387A）的小鼠自身不能裂解，它们的存活是可行的，而表达c-FLIP或CYLD蛋白的小鼠也已经突变，这些蛋白已经突变以防止被caspase-8裂解。相比之下，表达RIPK1（D325A）（其中caspase-8切割位点Asp325已突变）的小鼠在妊娠中期死亡。 RIPK1失活，TNFR1丢失或MLKL和caspase-8衔接子FADD都丢失可以防止胚胎致死，但不能单独丢失MLKL。因此，RIPK1（D325A）似乎触发了由TNF，RIPK1和FADD-caspase-8的激酶活性介导的细胞死亡。因此，在Ripk1（D325A / D325A）胚胎的卵黄囊中，含有裂解的caspase-3的垂死的内皮细胞异常丰富。杂合Ripk1（D325A / +）细胞和小鼠是可行的，但与野生型细胞或小鼠相比，更容易受到TNF诱导的细胞死亡。我们的数据表明RIPK1的Asp325对限制对TNF的异常细胞死亡至关重要，这与caspase-8裂解RIPK1是拆除引起死亡的复合物的机制的想法一致。

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