Caspase-8 signaling has proapoptotic, antinecroptotic, and proinflammatory signaling roles dependent on interaction with the adapter molecule FADD, oligomerization, and autocleavage. Previously, a Caspase-8 binding partner cFLIP L (FLIP, encoded by Cflar ) was shown to prevent Caspase-8-dependent apoptosis, but permit Caspase-8-dependent inhibition of necroptosis. We sought to explore the role of FLIP in Caspase-8-dependent apoptosis induction, necroptosis inhibition, and inflammatory signaling inhibition in vitro and in vivo. We provide evidence that in mice with a mutation that prevents Caspase-8 oligomerization ( Casp8 FGLG/FGLG ), FLIP is necessary to inhibit necroptosis, promote apoptosis, regulate inflammation, and control lymphoproliferative disease. Unlike Casp8 FGLG/FGLG mice, Casp8 FGLG/FGLG ,Cflar −/− mice do not survive embryogenesis, but ablation of Mlkl , required for necroptosis, allows their survival to adulthood. Further, unlike Casp8 FGLG/FGLG ,Mlkl −/− mice, Casp8 FGLG/FGLG ,Cflar −/− ,Mlkl −/− mice display lymphoproliferative disease. We analyzed apoptosis, necroptosis, and inflammatory signaling in Casp8 FGLG/FGLG mice with or without FLIP, gaining insights into the functions of the Caspase-8–FLIP heterodimer in vitro and in vivo.

中文翻译：

---

FLIP L 允许凋亡和炎症信号转导，并抑制无 Caspase-8 寡聚化的小鼠坏死性凋亡


Caspase-8 信号转导具有促凋亡、抗坏死和促炎信号转导作用，取决于与衔接分子 FADD 的相互作用、寡聚化和自溶裂解。以前，Caspase-8 结合伴侣 cFLIP L（FLIP，由 Cflar 编码）被证明可以防止 Caspase-8 依赖性细胞凋亡，但允许 Caspase-8 依赖性抑制坏死性凋亡。我们试图探索 FLIP 在体外和体内 Caspase-8 依赖性细胞凋亡诱导、坏死性凋亡抑制和炎症信号抑制中的作用。我们提供的证据表明，在具有阻止 Caspase-8 寡聚化 （Casp8 FGLG/FGLG） 突变的小鼠中，FLIP 对于抑制坏死性凋亡、促进细胞凋亡、调节炎症和控制淋巴组织增生性疾病是必要的。与 Casp8 FGLG/FGLG 小鼠不同，Casp8 FGLG/FGLG ，Cflar −/− 小鼠不能在胚胎发生中存活，但坏死性凋亡所需的 Mlkl 消融可以使它们存活到成年。此外，与 Casp8 FGLG/FGLG ，Mlkl −/− 小鼠不同，Casp8 FGLG/FGLG ，Cflar −/− 、Mlkl −/− 小鼠表现出淋巴组织增生性疾病。我们分析了有或没有 FLIP 的 Casp8 FGLG/FGLG 小鼠的细胞凋亡、坏死性凋亡和炎症信号，深入了解了 Caspase-8-FLIP 异二聚体在体外和体内的功能。