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The specificity of innate immune responses is enforced by repression of interferon response elements by NF-?B p50.

ABSTRACT: 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 ?B (NF-?B) and interferon (IFN) regulatory factor (IRF) transcription factor families bind to the ?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-?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-? was rendered stimulus-specific by the binding of the p50 homodimer to the G-IRE-containing IFN? enhancer to suppress cytotoxic IFN signaling. Specifically, a deficiency in p50 resulted in the inappropriate production of IFN-? in response to bacterial DNA sensed by Toll-like receptor 9. This role for the NF-?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-?B and IRF signaling systems cooperate to regulate antimicrobial immunity.

SUBMITTER: Cheng CS

PROVIDER: S-EPMC3096068 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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The specificity of innate immune responses is enforced by repression of interferon response elements by NF-κB p50.

Cheng Christine S CS Feldman Kristyn E KE Lee James J Verma Shilpi S Huang De-Bin DB Huynh Kim K Chang Mikyoung M Ponomarenko Julia V JV Sun Shao-Cong SC Benedict Chris A CA Ghosh Gourisankar G Hoffmann Alexander A

Science signaling 20110222 161

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 im ...[more]

PMID: 21343618

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Project description:About 8% of our genome is composed of sequences with viral origin, namely human Endogenous Retroviruses (HERVs). HERVs are relics of ancient infections that affected the primates' germ line along the last 100 million of years, and became stable elements at the interface between self and foreign DNA. Intriguingly, HERV co-evolution with the host led to the domestication of activities previously devoted to the retrovirus life cycle, providing novel cellular functions. For example, selected HERV envelope proteins have been coopted for pregnancy-related purposes, and proviral Long Terminal Repeats participate in the transcriptional regulation of various cellular genes. Given the HERV persistence in the host genome and its basal expression in most healthy tissues, it is reasonable that human defenses should prevent HERV-mediated immune activation. Despite this, HERVs and their products (including RNA, cytosolic DNA, and proteins) are still able to modulate and be influenced by the host immune system, fascinatingly suggesting a central role in the evolution and functioning of the human innate immunity. Indeed, HERV sequences had been major contributors in shaping and expanding the interferon network, dispersing inducible genes that have been occasionally domesticated in various mammalian lineages. Also the HERV integration within or near to genes encoding for critical immune factors has been shown to influence their activity, or to be responsible for their polymorphic variation in the human population, such as in the case of an HERV-K(HML10) provirus in the major histocompatibility complex region. In addition, HERV expressed products have been shown to modulate innate immunity effectors, being therefore often related on the one side to inflammatory and autoimmune disorders, while on the other side to the control of excessive immune activation through their immunosuppressive properties. Finally, HERVs have been proposed to establish a protective effect against exogenous infections. The present review summarizes the involvement of HERVs and their products in innate immune responses, describing how their intricate interplay with the first line of human defenses can actively contribute either to the host protection or to his damage, implying a subtle balance between the persistence of HERV expression and the maintenance of a basal immune alert.

Dataset Information

The specificity of innate immune responses is enforced by repression of interferon response elements by NF-?B p50.

Publications

The specificity of innate immune responses is enforced by repression of interferon response elements by NF-κB p50.

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