The specificity of innate immune responses is enforced by repression of interferon response elements by NF-κB p50.
The specificity of innate immune responses is enforced by repression of interferon response elements by NF-κB p50.
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DOI：
10.1126/scisignal.2001501
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发表时间：
2011-02-22
影响因子：
7.3
通讯作者：
Hoffmann A
中科院分区：
文献类型：
--
作者：
Cheng CS;Feldman KE;Lee J;Verma S;Huang DB;Huynh K;Chang M;Ponomarenko JV;Sun SC;Benedict CA;Ghosh G;Hoffmann A
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程序的关键。核因子κB和干扰素调节因子转录因子家族的成员分别与靶基因的κB位点和κ反应元件结合，并在接触病原体后在巨噬细胞中被激活。然而，这些因素如何产生病原体特异性的炎症和免疫反应仍然知之甚少。结合自上而下和自下而上的系统生物学方法，我们已经确定NF-κB p50同源二聚体是IRF反应的调节因子。全基因组无偏表达及生化和结构分析表明，p50同源二聚体通过富含鸟嘌呤的IRE(G-IRE)序列的一个亚类抑制了干扰素诱导基因的一个子集。数学模型预测，p50同源二聚体可能增强复合启动子的刺激特异性。事实上，通过将p50同源二聚体与含有G-IRE的干扰素β增强子结合来抑制细胞毒性干扰素信号，抗病毒调节因子干扰素-β的产生是刺激特异性的。具体地说，p50的缺失导致干扰素-β的不适当产生，以响应Toll样受体9感知的细菌DNA。这种NF-κB p50同源二聚体通过与IRE序列的子集结合来增强细胞对病原体的反应的这种作用改变了我们对NF-κB和IRF信号系统如何协同调节抗微生物免疫的理解。
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.
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DOI：
10.1126/science.1162327
发表时间：
2009-06-26
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Badis G;Berger MF;Philippakis AA;Talukder S;Gehrke AR;Jaeger SA;Chan ET;Metzler G;Vedenko A;Chen X;Kuznetsov H;Wang CF;Coburn D;Newburger DE;Morris Q;Hughes TR;Bulyk ML
通讯作者：
Bulyk ML
DOI：
10.1126/science.1179050
发表时间：
2009-10-09
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Amit I;Garber M;Chevrier N;Leite AP;Donner Y;Eisenhaure T;Guttman M;Grenier JK;Li W;Zuk O;Schubert LA;Birditt B;Shay T;Goren A;Zhang X;Smith Z;Deering R;McDonald RC;Cabili M;Bernstein BE;Rinn JL;Meissner A;Root DE;Hacohen N;Regev A
通讯作者：
Regev A
DOI：
10.1038/nsb0198-67
发表时间：
1998-01-01
期刊：
NATURE STRUCTURAL BIOLOGY
影响因子：
--
作者：
Chen, YQ;Ghosh, S;Ghosh, G
通讯作者：
Ghosh, G
影响因子：
64.8
作者：
GHOSH, G;VANDUYNE, G;SIGLER, PB
通讯作者：
SIGLER, PB
影响因子：
64.8
作者：
Foster, Simmie L.;Hargreaves, Diana C.;Medzhitov, Ruslan
通讯作者：
Medzhitov, Ruslan