Signaling Systems Laboratory, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Sci Signal. 2011 Feb 22;4(161):ra11. doi: 10.1126/scisignal.2001501.
The specific binding of transcription factors to cognate sequence elements is thought to be critical for the generation of specific gene expression programs. Members of the nuclear factor κB (NF-κB) and interferon (IFN) regulatory factor (IRF) transcription factor families bind to the κB site and the IFN response element (IRE), respectively, of target genes, and they are activated in macrophages after exposure to pathogens. However, how these factors produce pathogen-specific inflammatory and immune responses remains poorly understood. Combining top-down and bottom-up systems biology approaches, we have identified the NF-κB p50 homodimer as a regulator of IRF responses. Unbiased genome-wide expression and biochemical and structural analyses revealed that the p50 homodimer repressed a subset of IFN-inducible genes through a previously uncharacterized subclass of guanine-rich IRE (G-IRE) sequences. Mathematical modeling predicted that the p50 homodimer might enforce the stimulus specificity of composite promoters. Indeed, the production of the antiviral regulator IFN-β was rendered stimulus-specific by the binding of the p50 homodimer to the G-IRE-containing IFNβ enhancer to suppress cytotoxic IFN signaling. Specifically, a deficiency in p50 resulted in the inappropriate production of IFN-β in response to bacterial DNA sensed by Toll-like receptor 9. This role for the NF-κB p50 homodimer in enforcing the specificity of the cellular response to pathogens by binding to a subset of IRE sequences alters our understanding of how the NF-κB and IRF signaling systems cooperate to regulate antimicrobial immunity.
转录因子与同源序列元件的特异性结合被认为是产生特定基因表达谱的关键。核因子 kappa B（NF-κB）和干扰素（IFN）调节因子（IRF）转录因子家族的成员分别结合靶基因的κB 位点和 IFN 反应元件（IRE），并在巨噬细胞暴露于病原体后被激活。然而，这些因子如何产生针对病原体的炎症和免疫反应仍知之甚少。通过自上而下和自下而上的系统生物学方法相结合，我们发现 NF-κB p50 同源二聚体是 IRF 反应的调节剂。全面的基因组表达和生化及结构分析表明，p50 同源二聚体通过一个以前未被表征的富含鸟嘌呤的 IRE（G-IRE）序列亚类来抑制一组 IFN 诱导基因。数学模型预测，p50 同源二聚体可能通过结合包含 G-IRE 的 IFNβ 增强子来强制复合启动子的刺激特异性。事实上，p50 同源二聚体与包含 G-IRE 的 IFNβ 增强子结合，抑制细胞毒性 IFN 信号，从而使抗病毒调节剂 IFN-β 的产生具有刺激特异性。具体来说，p50 的缺乏导致 TLR9 检测到的细菌 DNA 引发的 IFN-β 不适当产生。NF-κB p50 同源二聚体通过与一组 IRE 序列结合，在对病原体的细胞反应中强制特异性，这改变了我们对 NF-κB 和 IRF 信号系统如何合作调节抗菌免疫的理解。
