| First Author | Yan Q | Year | 2012 |
| Journal | Proc Natl Acad Sci U S A | Volume | 109 |
| Issue | 35 | Pages | 14140-5 |
| PubMed ID | 22891325 | Mgi Jnum | J:188579 |
| Mgi Id | MGI:5441130 | Doi | 10.1073/pnas.1119842109 |
| Citation | Yan Q, et al. (2012) Nuclear factor-kappaB binding motifs specify Toll-like receptor-induced gene repression through an inducible repressosome. Proc Natl Acad Sci U S A 109(35):14140-5 |
| abstractText | 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-kappaB 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-kappaB motifs were the only regulatory elements significantly enriched in tolerizable genes. Mutating the NF-kappaB motifs of tolerizable genes converted them into nontolerizable ones, whereas inserting NF-kappaB binding motifs into nontolerizable genes conferred the tolerance. Although NF-kappaB 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-kappaB and the NcoR repressosome. |
