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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...

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Main Authors: Lee, Hwan Hee (Author) , Sanada, Satoru (Author) , An, Seung Min (Author) , Ye, Byeong Jin (Author) , Lee, Jun Ho (Author) , Seo, Young-Kyo (Author) , Lee, Changwook (Author) , Lee-Kwon, Whaseon (Author) , Küper, Christoph (Author) , Neuhofer, Wolfgang (Author) , Choi, Soo Youn (Author) , Kwon, Hyug Moo (Author)
Format: Article (Journal)
Language:English
Published: 27 April 2016
In: Scientific reports
Year: 2016, Volume: 6, Pages: 1-12
ISSN:2045-2322
DOI:10.1038/srep24921
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/srep24921
Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/srep24921
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Author Notes:Hwan Hee Lee, Satoru Sanada, Seung Min An, Byeong Jin Ye, Jun Ho Lee, Young-Kyo Seo, Changwook Lee, Whaseon Lee-Kwon, Christoph Küper, Wolfgang Neuhofer, Soo Youn Choi & Hyug Moo Kwon
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Summary: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.
Item Description:Gesehen am 17.06.2020
Physical Description:Online Resource
ISSN:2045-2322
DOI:10.1038/srep24921

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