LPS-induced NF?B enhanceosome requires TonEBP/NFAT5 without DNA binding.

ABSTRACT: NF?B is a central mediator of inflammation. Present inhibitors of NF?B 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 NF?B enhanceosome in which TonEBP is required for the recruitment of p300. Increased expression of TonEBP enhances the NF?B activity and reduced TonEBP expression lowers it. Recombinant TonEBP molecules incapable of recruiting p300 do not stimulate NF?B. 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 NF?B itself. Cerulenin suppresses the pro-inflammatory activation of macrophages and sepsis without detectable toxicity. Thus, the NF?B enhanceosome offers a promising target for useful anti-inflammatory agents.

SUBMITTER: Lee HH 

PROVIDER: S-EPMC4847014 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature