Nuclear factor-κB binding motifs specify Toll-like receptor-induced gene repression through an inducible repressosome.
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.
Department of Pathology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Qin
Q
Yan
Ruaidhri J
RJ
Carmody
Zhonghua
Z
Qu
Qingguo
Q
Ruan
Jennifer
J
Jager
Shannon E
SE
Mullican
Mitchell A
MA
Lazar
Youhai H
YH
Chen
D000107:Acetylation; D020816:Amino Acid Motifs / Q000276:immunology; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002460:Cell Line; D015870:Gene Expression / Q000276:immunology; D006655:Histone Deacetylases / Q000276:immunology / Q000378:metabolism; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D052002:NF-kappa B p50 Subunit / Q000276:immunology* / Q000378:metabolism; D056971:Nuclear Receptor Co-Repressor 1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D012772:Shock, Septic / Q000276:immunology / Q000517:prevention & control; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000099186:Histone Deacetylase 3
D006655:Histone Deacetylases; D008070:Lipopolysaccharides; D052002:NF-kappa B p50 Subunit; D056971:Nuclear Receptor Co-Repressor 1; D051197:Toll-Like Receptor 4; D000099186:Histone Deacetylase 3; C539128:Ncor1 protein, mouse; C493487:Tlr4 protein, mouse