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SIRT1 activators promote p65 deacetylation and suppress TNFa stimulated NF‐kB activation
Author(s) -
Yang Hongying,
Feldser Heidi Galonek,
Zhang Wei,
Zhong Zhong,
Loh Christine,
Ellis Jim
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.945.12
Subject(s) - acetylation , sirtuin 1 , chemistry , nf κb , downregulation and upregulation , gene knockdown , inflammation , hek 293 cells , microbiology and biotechnology , transcription factor , phosphorylation , nad+ kinase , iκbα , biochemistry , signal transduction , biology , enzyme , immunology , receptor , apoptosis , gene
NF‐κB is a transcription factor that mediates immune response and inflammation. The transcriptional activity of NF‐κB is regulated by inhibitor or coactivator proteins as well as posttranslational modifications such as phosphorylation and acetylation. SIRT1, a NAD + ‐dependent protein deacetylase, has been shown to deacetylate NF‐κB and suppress stimuli‐induced NF‐κB activation, which opens up a new avenue for treating inflammation through targeting of SIRT1. Our objective in this study was to evaluate SIRT1 and SIRT1 activators in regulating NF‐κB. We have developed a sensitive cellular assay in HEK293 cells to monitor acetylated p65. Consistent with previous reports, overexpression or inhibition of Sirt1 diminishes or escalates the levels of acetylated p65 respectively in these cells. In addition, we show that treatment of the cells with small molecule SIRT1 activators reduces acetylated p65 levels. Furthermore, the compound‐mediated drop in acetylated p65 can be partially reversed by knockdown or inhibition of SIRT1, indicating that the compound effects are dependent on SIRT1. We further demonstrate that these small molecule SIRT1 activators suppress transcriptional activity of NF‐κB induced by TNFα. In conclusion, our data show that small molecule SIRT1 activators mediate deacetylation of NF‐κB and downregulation of its transcription activity, further highlighting the potential use of SIRT1 activators to treat inflammatory diseases.