Modification of RelA by O-linked N-acetylglucosamine links glucose metabolism to NF-κB acetylation and transcription Academic Article uri icon

Overview

MeSH Major

  • Acetylglucosamine
  • Gene Expression Regulation
  • Glucose
  • Metabolic Networks and Pathways
  • NF-kappa B
  • Transcription Factor RelA

abstract

  • 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.

publication date

  • October 16, 2012

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3479489

Digital Object Identifier (DOI)

  • 10.1073/pnas.1208468109

PubMed ID

  • 23027940

Additional Document Info

start page

  • 16888

end page

  • 93

volume

  • 109

number

  • 42