Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
Sci Signal. 2013 Jan 15;6(258):pe2. doi: 10.1126/scisignal.2003845.
The anti-apoptotic protein c-FLIP, a catalytically inactive homolog of caspase-8, is an important regulator of death receptor signaling. Death receptors constitute a subgroup of the tumor necrosis factor receptor (TNFR) superfamily, which includes TNFR1, Fas, DR4, and DR5. When activated by their respective ligands, TNF, Fas ligand (FasL), and TNF-related apoptosis-inducing ligand (TRAIL), these receptors cause caspase-8-mediated apoptosis. If caspase-8 activity is blocked, however, then these receptors promote death by necroptosis (programmed necrosis), which requires the kinases receptor-interacting kinase 1 (RIPK1) and RIPK3, as well as mixed-lineage kinase-like protein. Necroptosis has become the subject of intense research because it promotes inflammation, and inhibiting this pathway can limit extensive tissue damage and even lethality in inflammatory syndromes. A study now reports on the role of c-FLIP in vivo from experiments with a range of conditional knockout mice and demonstrates that c-FLIP plays a critical role in inhibiting both apoptotic and necroptotic cell death within the whole mouse.
凋亡蛋白 c-FLIP 是半胱氨酸天冬氨酸蛋白酶（caspase）8 的无活性同工蛋白，属于抗凋亡蛋白家族，是死亡受体信号通路的重要调控因子。死亡受体属于肿瘤坏死因子受体（tumor necrosis factor receptor，TNFR）超家族的一个亚群，包括 TNFR1、Fas、DR4 和 DR5。当它们各自的配体 TNF、Fas 配体（FasL）和 TNF 相关凋亡诱导配体（TRAIL）与受体结合后，这些受体可诱导 caspase-8 介导的凋亡。然而，如果 caspase-8 的活性被阻断，这些受体则通过 necroptosis（程序性坏死）诱导细胞死亡，其需要激酶受体相互作用激酶 1（receptor-interacting kinase 1，RIPK1）和 RIPK3 以及混合谱系激酶样蛋白（mixed-lineage kinase-like protein）的参与。Necroptosis 已成为研究热点，因为它可促进炎症发生，抑制该通路可限制炎症综合征中广泛的组织损伤甚至致死性。一项研究通过一系列条件性基因敲除小鼠实验，报道了 c-FLIP 在体内的作用，并证实 c-FLIP 在抑制整个小鼠体内细胞凋亡和 necroptosis 方面发挥着关键作用。
