IRF-5 Is a Mediator of the Death Receptor-induced Apoptotic Signaling Pathway
IRF-5 Is a Mediator of the Death Receptor-induced Apoptotic Signaling Pathway
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DOI：
10.1074/jbc.m804744200
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发表时间：
2009-01-30
影响因子：
4.8
通讯作者：
Barnes, Betsy J.
中科院分区：
文献类型：
--
作者：
Hu, Guodong;Barnes, Betsy J.
对细胞应激的有效和受调节的反应是由遗传调控网络协调的，其中给定的转录因子根据细胞类型和/或刺激的性质控制不同靶基因的表达。肿瘤抑制因子 p53 被认为优先调节细胞生存和死亡之间的平衡。干扰素调节因子 5 (IRF-5) 已知参与对病原体的先天免疫反应，也是 DNA 损伤诱导细胞凋亡的关键调节因子。在这里，我们提供了直接证据表明 IRF-5 通过肿瘤坏死因子相关凋亡诱导配体 (TRAIL) 死亡受体 (DR) 信号传导促进细胞凋亡。我们报告说，IRF-5 使肿瘤细胞对 TRAIL 诱导的细胞凋亡和细胞死亡敏感，而 I 型干扰素进一步增强了这种作用。缺乏 IRF-5 的细胞对这些药物的反应显着减弱。 IRF-5 参与 caspase 8 上游的 DR 信号传导，部分原因是 IRF-5 依赖性 caspase 8 激活增加。我们提供的证据表明，TRAIL 诱导信号级联反应，导致 IRF-5 磷酸化和核定位，从而导致关键 DR 信号传导成分的反式激活。本文提出的结果将 IRF-5 确定为 DR 信号传导的新介质，并提供了对 TRAIL 诱导的 IRF-5 信号传导机制的分子见解。
The efficient and regulated response to cellular stress is coordinated by a genetic regulatory network in which a given transcription factor controls the expression of diverse target genes depending on the cell type and/or nature of the stimuli. The tumor suppressor p53 is thought to preferentially regulate the balance between cell survival and death. The interferon regulatory factor 5 (IRF-5), known to be involved in the innate immune response to pathogens, is also a critical regulator of DNA damage-induced apoptosis. Here, we provide direct evidence that IRF-5 promotes apoptosis upon signaling through tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptors (DR). We report that IRF-5 sensitizes tumor cells to TRAIL-induced apoptosis and cell death that is further enhanced by type I interferons. Cells deficient of IRF-5 gave a significantly diminished response to these agents. IRF-5 is involved in DR signaling upstream of caspase 8, in part because of an IRF-5-dependent increase in caspase 8 activation. We provide evidence that TRAIL induces a signaling cascade that leads to the phosphorylation and nuclear localization of IRF-5, resulting in transactivation of key DR signaling components. The results presented here identify IRF-5 as a new mediator of DR signaling and provides molecular insight into the mechanism of TRAIL-induced IRF-5 signaling.