Abstract：
Perturbation of the apoptosis and necroptosis pathways critically influences embryogenesis. Receptor-associated protein kinase-1 (RIPK1) interacts with Fas-associated via death domain (FADD)-caspase-8-cellular Flice-like inhibitory protein long (cFLIPL) to regulate both extrinsic apoptosis and necroptosis. Here, we describe Ripk1-mutant animals (Ripk1R588E [RE]) in which the interaction between FADD and RIPK1 is disrupted, leading to embryonic lethality. This lethality is not prevented by further removal of the kinase activity of Ripk1 (Ripk1R588E K45A [REKA]). Both Ripk1RE and Ripk1REKA animals survive to adulthood upon ablation of Ripk3. While embryonic lethality of Ripk1RE mice is prevented by ablation of the necroptosis effector mixed lineage kinase-like (MLKL), animals succumb to inflammation after birth. In contrast, Mlkl ablation does not prevent the death of Ripk1REKA embryos, but animals reach adulthood when both MLKL and caspase-8 are removed. Ablation of the nucleic acid sensor Zbp1 largely prevents lethality in both Ripk1RE and Ripk1REKA embryos. Thus, the RIPK1-FADD interaction prevents Z-DNA binding protein-1 (ZBP1)-induced, RIPK3-caspase-8-mediated embryonic lethality, affected by the kinase activity of RIPK1.
摘要：
凋亡和坏死途径的扰动严重影响胚胎发生。受体相关蛋白激酶1（RIPK1）通过死亡结构域（FADD）-caspase-8细胞Flice样抑制蛋白（cFLIPL）与Fas相关相互作用，以调节外源性凋亡和坏死。这里,我们描述了Ripk1突变动物（Ripk1R588E[RE]），其中FADD和RIPK1之间的相互作用被破坏，导致胚胎致死。通过进一步去除Ripk1的激酶活性(Ripk1R588EK45A[REKA])不能防止这种致死性。Ripk1RE和Ripk1REKA动物均在Ripk3消融后存活至成年。虽然Ripk1RE小鼠的胚胎致死率可通过去除坏死效应子混合谱系激酶样（MLKL）来防止，动物出生后屈服于炎症。相比之下,Mlkl消融并不能阻止Ripk1REKA胚胎的死亡，但是当MLKL和caspase-8都被移除时，动物达到成年。核酸传感器Zbp1的消融在很大程度上防止了Ripk1RE和Ripk1REKA胚胎中的致死性。因此，RIPK1-FADD相互作用阻止Z-DNA结合蛋白-1（ZBP1）诱导，RIPK3-caspase-8介导的胚胎致死性，受RIPK1激酶活性的影响。
