The c-FLIPL Cleavage Product p43FLIP Promotes Activation of Extracellular Signal-regulated Kinase (ERK), Nuclear Factor κB (NF-κB), and Caspase-8 and T Cell Survival
The c-FLIPL Cleavage Product p43FLIP Promotes Activation of Extracellular Signal-regulated Kinase (ERK), Nuclear Factor κB (NF-κB), and Caspase-8 and T Cell Survival
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DOI：
10.1074/jbc.m113.506428
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发表时间：
2014-01-10
影响因子：
4.8
通讯作者：
Budd, Ralph C.
中科院分区：
文献类型：
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作者：
Koenig, Andreas;Buskiewicz, Iwona A.;Budd, Ralph C.
现在认识到胱天蛋白酶-8通过抑制核糖体来控制死亡受体连接后的细胞凋亡和细胞存活和生长。因此，细胞必须小心地调节细胞凋亡过程中高水平的caspase-8活性，而不是细胞生长过程中观察到的中等水平。caspase-8 para-FLIP是一个很好的候选人的caspase-8活性的分子变阻器。c-FLIP可以通过与caspase-8竞争募集FADD来抑制死亡受体介导的凋亡。然而，全长c-FLIPL也可以与胱天蛋白酶-8异二聚化，而不依赖于死亡受体连接，并通过c-FLIPL C末端的活化环活化胱天蛋白酶-8。这触发c-FLIPL在Asp-376处被半胱天冬酶-8切割以产生p43 FLIP。然而，p43 FLIP的持续功能尚未确定。我们证明，在小鼠效应T细胞中内源性c-FLIP的急性缺失导致caspase-8活性的丧失和细胞死亡。p43 FLIP的转基因表达可以挽救细胞的致死率和caspase-8活性。此外，p43 FLIP与Raf 1、TRAF 2和RIPK 1相关，其增强ERK和NF-κ B活化、IL-2产生和T细胞增殖。因此，c-FLIP不仅是T细胞活化过程中胱天蛋白酶-8活性的引发剂，它也是初始胱天蛋白酶-8底物，裂解的p43 FLIP用于稳定胱天蛋白酶-8活性并促进与T细胞生长有关的途径的活化。
Caspase-8 is now appreciated to govern both apoptosis following death receptor ligation and cell survival and growth via inhibition of the Ripoptosome. Cells must therefore carefully regulate the high level of caspase-8 activity during apoptosis versus the modest levels observed during cell growth. The caspase-8 paralogue c-FLIP is a good candidate for a molecular rheostat of caspase-8 activity. c-FLIP can inhibit death receptor-mediated apoptosis by competing with caspase-8 for recruitment to FADD. However, full-length c-FLIPL can also heterodimerize with caspase-8 independent of death receptor ligation and activate caspase-8 via an activation loop in the C terminus of c-FLIPL. This triggers cleavage of c-FLIPL at Asp-376 by caspase-8 to produce p43FLIP. The continued function of p43FLIP has, however, not been determined. We demonstrate that acute deletion of endogenous c-FLIP in murine effector T cells results in loss of caspase-8 activity and cell death. The lethality and caspase-8 activity can both be rescued by the transgenic expression of p43FLIP. Furthermore, p43FLIP associates with Raf1, TRAF2, and RIPK1, which augments ERK and NF-kappa B activation, IL-2 production, and T cell proliferation. Thus, not only is c-FLIP the initiator of caspase-8 activity during T cell activation, it is also an initial caspase-8 substrate, with cleaved p43FLIP serving to both stabilize caspase-8 activity and promote activation of pathways involved with T cell growth.