Hu Guodong, Barnes Betsy J
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland 21231; New Jersey Medical School-University Hospital Cancer Center, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07103.
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland 21231; New Jersey Medical School-University Hospital Cancer Center, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07103; Department of Biochemistry & Molecular Biology, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07103.
J Biol Chem. 2009 Jan 30;284(5):2767-2777. doi: 10.1074/jbc.M804744200. Epub 2008 Nov 20.
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.
细胞应激的有效且受调控的反应由一个基因调控网络协调，在该网络中，特定的转录因子根据细胞类型和/或刺激的性质控制多种靶基因的表达。肿瘤抑制因子p53被认为优先调节细胞存活与死亡之间的平衡。干扰素调节因子5（IRF-5），已知参与对病原体的固有免疫反应，也是DNA损伤诱导的细胞凋亡的关键调节因子。在此，我们提供直接证据表明，IRF-5通过肿瘤坏死因子相关凋亡诱导配体（TRAIL）死亡受体（DR）发出信号时促进细胞凋亡。我们报告称，IRF-5使肿瘤细胞对TRAIL诱导的细胞凋亡和细胞死亡敏感，且I型干扰素可进一步增强这种敏感性。缺乏IRF-5的细胞对这些因子的反应明显减弱。IRF-5参与caspase 8上游的DR信号传导，部分原因是IRF-5依赖性地增加了caspase 8的激活。我们提供证据表明，TRAIL诱导一个信号级联反应，导致IRF-5的磷酸化和核定位，从而导致关键DR信号成分的反式激活。此处呈现的结果确定IRF-5为DR信号传导的新介质，并为TRAIL诱导的IRF-5信号传导机制提供了分子层面的见解。
