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Sci Rep. 2016 Apr 27;6:24921. doi: 10.1038/srep24921.

LPS-induced NFκB enhanceosome requires TonEBP/NFAT5 without DNA binding.

Author information

1
School of Life Sciences, Ulsan National Institute of Science and Technology, Korea.
2
Division of Nephrology, Japan Community Care Organization Sendai Hospital, Japan.
3
Institute of Physiology, University of Munich, Germany.
4
Department of Medicine, Heidelberg University, Germany.

Abstract

NFκB is a central mediator of inflammation. Present inhibitors of NFκB are mostly based on inhibition of essential machinery such as proteasome and protein kinases, or activation of nuclear receptors; as such, they are of limited therapeutic use due to severe toxicity. Here we report an LPS-induced NFκB enhanceosome in which TonEBP is required for the recruitment of p300. Increased expression of TonEBP enhances the NFκB activity and reduced TonEBP expression lowers it. Recombinant TonEBP molecules incapable of recruiting p300 do not stimulate NFκB. Myeloid-specific deletion of TonEBP results in milder inflammation and sepsis. We discover that a natural small molecule cerulenin specifically disrupts the enhanceosome without affecting the activation of NFκB itself. Cerulenin suppresses the pro-inflammatory activation of macrophages and sepsis without detectable toxicity. Thus, the NFκB enhanceosome offers a promising target for useful anti-inflammatory agents.

PMID:
27118681
PMCID:
PMC4847014
DOI:
10.1038/srep24921
[Indexed for MEDLINE]
Free PMC Article

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