A fas-associated death domain protein/caspase-8-signaling axis promotes S-phase entry and maintains S6 kinase activity in T cells responding to IL-2
A fas-associated death domain protein/caspase-8-signaling axis promotes S-phase entry and maintains S6 kinase activity in T cells responding to IL-2
复制标题
DOI：
10.4049/jimmunol.179.8.5291
复制
发表时间：
2007-10-15
影响因子：
4.4
通讯作者：
Walsh, Craig M.
中科院分区：
文献类型：
--
作者：
Arechiga, Adrian F.;Bell, Bryan D.;Walsh, Craig M.
Fas 相关死亡结构域蛋白 (FADD) 是 TNFR 诱导的细胞凋亡信号传导的重要组成部分。矛盾的是，FADD 也被证明对淋巴细胞的发育和激活至关重要。在这项研究中，我们报告 FADD 对于长期维持 S6 激酶 (S6K) 活性是必需的。丝氨酸 240 和 244 处的 S6 磷酸化仅在野生型细胞长期刺激后观察到，大致相当于进入 S 期之前的时间，并且在表达显性干扰形式 FADD (FADDdd)、病毒 FLIP 或具有 caspase-8 缺陷的 T 细胞中诱导较差。还观察到 S6K1 磷酸化缺陷。然而，S6K1 磷酸化缺陷并不是哺乳动物雷帕霉素功能靶标整体缺陷的结果，因为 T 细胞激活后的 4E-BP1 磷酸化不受 FADDdd 表达的影响。尽管 FADDdd T 细胞中细胞周期蛋白 D3 上调和视网膜母细胞瘤低磷酸化正常发生，但 FADDdd T 细胞中细胞周期蛋白 E 表达和细胞周期蛋白依赖性激酶 2 激活明显受损。这些结果表明 FADD/caspase-8 信号轴促进 T 细胞周期进展和持续的 S6K 活性。
Fas-associated death domain protein (FADD) constitutes an essential component of TNFR-induced apoptotic signaling. Paradoxically, FADD has also been shown to be crucial for lymphocyte development and activation. In this study, we report that FADD is necessary for long-term maintenance of S6 kinase (S6K) activity. S6 phosphorylation at serines 240 and 244 was only observed after long-term stimulation of wild-type cells, roughly corresponding to the time before S-phase entry, and was poorly induced in T cells expressing a dominantly interfering form of FADD (FADDdd), viral FLIP, or possessing a deficiency in caspase-8. Defects in S6K1 phosphorylation were also observed. However, defective S6K1 phosphorylation was not a consequence of a wholesale defect in mammalian target of rapamycin function, because 4E-BP1 phosphorylation following T cell activation was unaffected by FADDdd expression. Although cyclin D3 up-regulation and retinoblastoma hypophosphorylation occurred normally in FADDdd T cells, cyclin E expression and cyclin-dependent kinase 2 activation were markedly impaired in FADDdd T cells. These results demonstrate that a FADD/caspase-8-signaling axis promotes T cell cycle progression and sustained S6K activity.