Nuclear factor- B 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. and Chen, Y.H. (2012) Nuclear factor- B binding motifs specify Toll-like receptor-induced gene repression through an inducible repressosome. Proceedings of the National Academy of Sciences of the United States of America, 109(35), pp. 14140-14145. (doi: 10.1073/pnas.1119842109)

Abstract

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Carmody, Dr Ruaidhri
• Authors: Yan, Q., Carmody, R.J., Qu, Z., Ruan, Q., Jager, J., Mullican, S.E., Lazar, M.A., and Chen, Y.H.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Proceedings of the National Academy of Sciences of the United States of America
• Journal Abbr.: Proc. Natl. Acad. Sci.
• Publisher: National Academy of Sciences
• ISSN: 0027-8424
• ISSN (Online): 1091-6490
• Published Online: 13 August 2012