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Modification of RelA by O-linked N-acetylglucosamine links glucose metabolism to NF-?B acetylation and transcription.

ABSTRACT: The molecular mechanisms linking glucose metabolism with active transcription remain undercharacterized in mammalian cells. Using nuclear factor-?B (NF-?B) as a glucose-responsive transcription factor, we show that cells use the hexosamine biosynthesis pathway and O-linked ?-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-?B-regulated promoters to enhance RelA acetylation. Knockdown of OGT abolishes p300-mediated acetylation of RelA on K310, a posttranslational mark required for full NF-?B 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-?B. Reconstitution of RelA null cells with the RelA(T305A) mutant illustrates the importance of this residue for NF-?B-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-?B transcription.

SUBMITTER: Allison DF 

PROVIDER: S-EPMC3479489 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Modification of RelA by O-linked N-acetylglucosamine links glucose metabolism to NF-κB acetylation and transcription.

Allison David F DF   Wamsley J Jacob JJ   Kumar Manish M   Li Duo D   Gray Lisa G LG   Hart Gerald W GW   Jones David R DR   Mayo Marty W MW  

Proceedings of the National Academy of Sciences of the United States of America 20121001 42

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  ...[more]