The molecular mechanisms linking glucose metabolism with active transcription remain undercharacterized in mammalian cells. Using nuclear factor-κB (NF-κB) as a glucose-responsive transcription factor, we show that cells use the hexosamine biosynthesis pathway and O-linked β-N-acetylglucosamine (O-GlcNAc) transferase (OGT) to potentiate gene expression in response to tumor necrosis factor (TNF) or etoposide. Chromatin immunoprecipitation assays demonstrate that, upon induction, OGT localizes to NF-κB-regulated promoters to enhance RelA acetylation. Knockdown of OGT abolishes p300-mediated acetylation of RelA on K310, a posttranslational mark required for full NF-κB transcription. Mapping studies reveal T305 as an important residue required for attachment of the O-GlcNAc moiety on RelA. Furthermore, p300 fails to acetylate a full-length RelA(T305A) mutant, linking O-GlcNAc and acetylation events on NF-κB. Reconstitution of RelA null cells with the RelA(T305A) mutant illustrates the importance of this residue for NF-κB-dependent gene expression and cell survival. Our work provides evidence for a unique regulation where attachment of the O-GlcNAc moiety to RelA potentiates p300 acetylation and NF-κB transcription.
|Original language||English (US)|
|Number of pages||6|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|State||Published - Oct 16 2012|
- NF kappa B
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