期刊
SCIENCE SIGNALING
卷 4, 期 161, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.2001501
关键词
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资金
- NIAID NIH HHS [R01 AI057555-09, R56 AI069298-01A2, AI069298, AI057555, R21 AI076864-02, R56 AI069298, AI076864, R21 AI076864, R01 AI083453, R01 AI057555] Funding Source: Medline
- NIGMS NIH HHS [R01 GM071573, R01 GM085490, GM085490, P50 GM085764, P50 GM085764-02, GM085325, R01 GM085325, R01 GM085325-04, R01 GM071573-07, GM071573, R01 GM085490-04, P50-GM085764] Funding Source: Medline
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 kappa B (NF-kappa B) and interferon (IFN) regulatory factor (IRF) transcription factor families bind to the kappa B 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-kappa B 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-beta was rendered stimulus-specific by the binding of the p50 homodimer to the G-IRE-containing IFN beta enhancer to suppress cytotoxic IFN signaling. Specifically, a deficiency in p50 resulted in the inappropriate production of IFN-beta in response to bacterial DNA sensed by Toll-like receptor 9. This role for the NF-kappa B 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-kappa B and IRF signaling systems cooperate to regulate antimicrobial immunity.
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