LPS-induced NFκB enhanceosome requires TonEBP/NFAT5 without DNA binding.
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.
School of Life Sciences, Ulsan National Institute of Science and Technology, Korea.
Hwan Hee
HH
Lee
Division of Nephrology, Japan Community Care Organization Sendai Hospital, Japan.
Satoru
S
Sanada
School of Life Sciences, Ulsan National Institute of Science and Technology, Korea.
Seung Min
SM
An
School of Life Sciences, Ulsan National Institute of Science and Technology, Korea.
Byeong Jin
BJ
Ye
School of Life Sciences, Ulsan National Institute of Science and Technology, Korea.
Jun Ho
JH
Lee
School of Life Sciences, Ulsan National Institute of Science and Technology, Korea.
Young-Kyo
YK
Seo
School of Life Sciences, Ulsan National Institute of Science and Technology, Korea.
Changwook
C
Lee
School of Life Sciences, Ulsan National Institute of Science and Technology, Korea.
Whaseon
W
Lee-Kwon
Institute of Physiology, University of Munich, Germany.
Christoph
C
Küper
Department of Medicine, Heidelberg University, Germany.
Wolfgang
W
Neuhofer
School of Life Sciences, Ulsan National Institute of Science and Technology, Korea.
Soo Youn
SY
Choi
School of Life Sciences, Ulsan National Institute of Science and Technology, Korea.
Hyug Moo
HM
Kwon
D000818:Animals; D002569:Cerulenin / Q000378:metabolism; D002522:Chlorocebus aethiops; D004247:DNA / Q000378:metabolism*; D050881:E1A-Associated p300 Protein / Q000378:metabolism*; D006801:Humans; D008070:Lipopolysaccharides / Q000276:immunology*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
D008070:Lipopolysaccharides; D016328:NF-kappa B; C492200:Nfat5 protein, mouse; D014157:Transcription Factors; D002569:Cerulenin; D004247:DNA; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse