Nuclear factor-κB binding motifs specify Toll-like receptor-induced gene repression through an inducible repressosome

Yan Q.; Carmody R.J.; Qu Z.Ruan Q.Jager J.Mullican S.E.Lazar M.A.Chen Y.H.

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Nuclear factor-κB binding motifs specify Toll-like receptor-induced gene repression through an inducible repressosome

机译：Nuclear factor-κB binding motifs specify Toll-like receptor-induced gene repression through an inducible repressosome

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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 anNcoR-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 theminto 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.

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《Proceedings of the National Academy of Sciences of the United States of America》 |2012年第35期|14140-14145|共6页
作者
Yan Q.; Carmody R.J.; Qu Z.Ruan Q.Jager J.Mullican S.E.Lazar M.A.Chen Y.H.;
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Department of Pathology and Laboratory of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, United States;

Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, United States;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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正文语种英语
中图分类自然科学总论;
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Nuclear factor-κB binding motifs specify Toll-like receptor-induced gene repression through an inducible repressosome

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