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Nuclear factor-κB binding motifs specify Toll-like receptor-induced gene repression through an inducible repressosome
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| Zeitschriftentitel: | Proceedings of the National Academy of Sciences |
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| Personen und Körperschaften: | , , , , , , , |
| In: | Proceedings of the National Academy of Sciences, 109, 2012, 35, S. 14140-14145 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
Proceedings of the National Academy of Sciences
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| Schlagwörter: |
| author_facet |
Yan, Qin Carmody, Ruaidhri J. Qu, Zhonghua Ruan, Qingguo Jager, Jennifer Mullican, Shannon E. Lazar, Mitchell A. Chen, Youhai H. Yan, Qin Carmody, Ruaidhri J. Qu, Zhonghua Ruan, Qingguo Jager, Jennifer Mullican, Shannon E. Lazar, Mitchell A. Chen, Youhai H. |
|---|---|
| author |
Yan, Qin Carmody, Ruaidhri J. Qu, Zhonghua Ruan, Qingguo Jager, Jennifer Mullican, Shannon E. Lazar, Mitchell A. Chen, Youhai H. |
| spellingShingle |
Yan, Qin Carmody, Ruaidhri J. Qu, Zhonghua Ruan, Qingguo Jager, Jennifer Mullican, Shannon E. Lazar, Mitchell A. Chen, Youhai H. Proceedings of the National Academy of Sciences Nuclear factor-κB binding motifs specify Toll-like receptor-induced gene repression through an inducible repressosome Multidisciplinary |
| author_sort |
yan, qin |
| spelling |
Yan, Qin Carmody, Ruaidhri J. Qu, Zhonghua Ruan, Qingguo Jager, Jennifer Mullican, Shannon E. Lazar, Mitchell A. Chen, Youhai H. 0027-8424 1091-6490 Proceedings of the National Academy of Sciences Multidisciplinary http://dx.doi.org/10.1073/pnas.1119842109 <jats:p>Sustained Toll-like receptor (TLR) stimulation continuously activates antimicrobial genes but paradoxically represses inflammatory genes. This phenomenon, termed TLR tolerance, is essential for preventing fatal inflammatory conditions such as sepsis, but its underlying mechanisms are unclear. We report here that NF-κB binding nucleic acids of gene promoters are tolerogenic motifs, which selectively recruit an NcoR–Hdac3–deacetylated-p50 repressosome to inflammatory genes. Genome-wide analyses of TLR4-induced genes revealed that NF-κB motifs were the only regulatory elements significantly enriched in tolerizable genes. Mutating the NF-κB motifs of tolerizable genes converted them into nontolerizable ones, whereas inserting NF-κB binding motifs into nontolerizable genes conferred the tolerance. Although NF-κB p50 was essential for assembling the repressosome, genetic disruption of the NcoR–Hdac3 interaction alone was sufficient to completely abolish TLR4 tolerance and to render mice vulnerable to sepsis. Thus, the specificity of TLR tolerance is dictated by evolutionally conserved nucleic acid motifs that bound by NF-κB and the NcoR repressosome.</jats:p> Nuclear factor-κB binding motifs specify Toll-like receptor-induced gene repression through an inducible repressosome Proceedings of the National Academy of Sciences |
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| title |
Nuclear factor-κB binding motifs specify Toll-like receptor-induced gene repression through an inducible repressosome |
| title_unstemmed |
Nuclear factor-κB binding motifs specify Toll-like receptor-induced gene repression through an inducible repressosome |
| title_full |
Nuclear factor-κB binding motifs specify Toll-like receptor-induced gene repression through an inducible repressosome |
| title_fullStr |
Nuclear factor-κB binding motifs specify Toll-like receptor-induced gene repression through an inducible repressosome |
| title_full_unstemmed |
Nuclear factor-κB binding motifs specify Toll-like receptor-induced gene repression through an inducible repressosome |
| title_short |
Nuclear factor-κB binding motifs specify Toll-like receptor-induced gene repression through an inducible repressosome |
| title_sort |
nuclear factor-κb binding motifs specify toll-like receptor-induced gene repression through an inducible repressosome |
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Multidisciplinary |
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http://dx.doi.org/10.1073/pnas.1119842109 |
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2012 |
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14140-14145 |
| description |
<jats:p>Sustained Toll-like receptor (TLR) stimulation continuously activates antimicrobial genes but paradoxically represses inflammatory genes. This phenomenon, termed TLR tolerance, is essential for preventing fatal inflammatory conditions such as sepsis, but its underlying mechanisms are unclear. We report here that NF-κB binding nucleic acids of gene promoters are tolerogenic motifs, which selectively recruit an NcoR–Hdac3–deacetylated-p50 repressosome to inflammatory genes. Genome-wide analyses of TLR4-induced genes revealed that NF-κB motifs were the only regulatory elements significantly enriched in tolerizable genes. Mutating the NF-κB motifs of tolerizable genes converted them into nontolerizable ones, whereas inserting NF-κB binding motifs into nontolerizable genes conferred the tolerance. Although NF-κB p50 was essential for assembling the repressosome, genetic disruption of the NcoR–Hdac3 interaction alone was sufficient to completely abolish TLR4 tolerance and to render mice vulnerable to sepsis. Thus, the specificity of TLR tolerance is dictated by evolutionally conserved nucleic acid motifs that bound by NF-κB and the NcoR repressosome.</jats:p> |
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| author | Yan, Qin, Carmody, Ruaidhri J., Qu, Zhonghua, Ruan, Qingguo, Jager, Jennifer, Mullican, Shannon E., Lazar, Mitchell A., Chen, Youhai H. |
| author_facet | Yan, Qin, Carmody, Ruaidhri J., Qu, Zhonghua, Ruan, Qingguo, Jager, Jennifer, Mullican, Shannon E., Lazar, Mitchell A., Chen, Youhai H., Yan, Qin, Carmody, Ruaidhri J., Qu, Zhonghua, Ruan, Qingguo, Jager, Jennifer, Mullican, Shannon E., Lazar, Mitchell A., Chen, Youhai H. |
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| description | <jats:p>Sustained Toll-like receptor (TLR) stimulation continuously activates antimicrobial genes but paradoxically represses inflammatory genes. This phenomenon, termed TLR tolerance, is essential for preventing fatal inflammatory conditions such as sepsis, but its underlying mechanisms are unclear. We report here that NF-κB binding nucleic acids of gene promoters are tolerogenic motifs, which selectively recruit an NcoR–Hdac3–deacetylated-p50 repressosome to inflammatory genes. Genome-wide analyses of TLR4-induced genes revealed that NF-κB motifs were the only regulatory elements significantly enriched in tolerizable genes. Mutating the NF-κB motifs of tolerizable genes converted them into nontolerizable ones, whereas inserting NF-κB binding motifs into nontolerizable genes conferred the tolerance. Although NF-κB p50 was essential for assembling the repressosome, genetic disruption of the NcoR–Hdac3 interaction alone was sufficient to completely abolish TLR4 tolerance and to render mice vulnerable to sepsis. Thus, the specificity of TLR tolerance is dictated by evolutionally conserved nucleic acid motifs that bound by NF-κB and the NcoR repressosome.</jats:p> |
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| imprint_str_mv | Proceedings of the National Academy of Sciences, 2012 |
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| spelling | Yan, Qin Carmody, Ruaidhri J. Qu, Zhonghua Ruan, Qingguo Jager, Jennifer Mullican, Shannon E. Lazar, Mitchell A. Chen, Youhai H. 0027-8424 1091-6490 Proceedings of the National Academy of Sciences Multidisciplinary http://dx.doi.org/10.1073/pnas.1119842109 <jats:p>Sustained Toll-like receptor (TLR) stimulation continuously activates antimicrobial genes but paradoxically represses inflammatory genes. This phenomenon, termed TLR tolerance, is essential for preventing fatal inflammatory conditions such as sepsis, but its underlying mechanisms are unclear. We report here that NF-κB binding nucleic acids of gene promoters are tolerogenic motifs, which selectively recruit an NcoR–Hdac3–deacetylated-p50 repressosome to inflammatory genes. Genome-wide analyses of TLR4-induced genes revealed that NF-κB motifs were the only regulatory elements significantly enriched in tolerizable genes. Mutating the NF-κB motifs of tolerizable genes converted them into nontolerizable ones, whereas inserting NF-κB binding motifs into nontolerizable genes conferred the tolerance. Although NF-κB p50 was essential for assembling the repressosome, genetic disruption of the NcoR–Hdac3 interaction alone was sufficient to completely abolish TLR4 tolerance and to render mice vulnerable to sepsis. Thus, the specificity of TLR tolerance is dictated by evolutionally conserved nucleic acid motifs that bound by NF-κB and the NcoR repressosome.</jats:p> Nuclear factor-κB binding motifs specify Toll-like receptor-induced gene repression through an inducible repressosome Proceedings of the National Academy of Sciences |
| spellingShingle | Yan, Qin, Carmody, Ruaidhri J., Qu, Zhonghua, Ruan, Qingguo, Jager, Jennifer, Mullican, Shannon E., Lazar, Mitchell A., Chen, Youhai H., Proceedings of the National Academy of Sciences, Nuclear factor-κB binding motifs specify Toll-like receptor-induced gene repression through an inducible repressosome, Multidisciplinary |
| title | Nuclear factor-κB binding motifs specify Toll-like receptor-induced gene repression through an inducible repressosome |
| title_full | Nuclear factor-κB binding motifs specify Toll-like receptor-induced gene repression through an inducible repressosome |
| title_fullStr | Nuclear factor-κB binding motifs specify Toll-like receptor-induced gene repression through an inducible repressosome |
| title_full_unstemmed | Nuclear factor-κB binding motifs specify Toll-like receptor-induced gene repression through an inducible repressosome |
| title_short | Nuclear factor-κB binding motifs specify Toll-like receptor-induced gene repression through an inducible repressosome |
| title_sort | nuclear factor-κb binding motifs specify toll-like receptor-induced gene repression through an inducible repressosome |
| title_unstemmed | Nuclear factor-κB binding motifs specify Toll-like receptor-induced gene repression through an inducible repressosome |
| topic | Multidisciplinary |
| url | http://dx.doi.org/10.1073/pnas.1119842109 |