Activation of the transcriptional function of the NF-κB protein c-Rel by O-GlcNAc glycosylation

Sci Signal. 2013 Aug 27;6(290):ra75. doi: 10.1126/scisignal.2004097.


The transcription factor nuclear factor κB (NF-κB) rapidly reprograms gene expression in response to various stimuli, and its activity is regulated by several posttranslational modifications, including phosphorylation, methylation, and acetylation. The addition of O-linked β-N-acetylglucosamine (a process known as O-GlcNAcylation) is an abundant posttranslational modification that is enhanced in conditions such as hyperglycemia and cellular stress. We report that the NF-κB subunit c-Rel is modified and activated by O-GlcNAcylation. We identified serine 350 as the site of O-GlcNAcylation, which was required for the DNA binding and transactivation functions of c-Rel. Blocking the O-GlcNAcylation of this residue abrogated c-Rel-mediated expression of the cytokine-encoding genes IL2, IFNG, and CSF2 in response to T cell receptor (TCR) activation, whereas increasing the extent of O-GlcNAcylation of cellular proteins enhanced the expression of these genes. TCR- or tumor necrosis factor (TNF)-induced expression of other NF-κB target genes, such as NFKBIA (which encodes IκBα) and TNFAIP3 (which encodes A20), occurred independently of the O-GlcNAcylation of c-Rel. Our findings suggest a stimulus-specific role for hyperglycemia-induced O-GlcNAcylation of c-Rel in promoting T cell-mediated autoimmunity in conditions such as type 1 diabetes by enhancing the production of T helper cell cytokines.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylglucosamine / metabolism*
  • Acylation
  • Animals
  • Binding Sites / genetics
  • Blotting, Western
  • Cell Line, Tumor
  • Cells, Cultured
  • Glycosylation
  • Granulocyte-Macrophage Colony-Stimulating Factor / genetics
  • Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
  • HEK293 Cells
  • Humans
  • Interferon-gamma / genetics
  • Interferon-gamma / metabolism
  • Interleukin-2 / genetics
  • Interleukin-2 / metabolism
  • Jurkat Cells
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Protein Binding
  • Proto-Oncogene Proteins c-rel / genetics
  • Proto-Oncogene Proteins c-rel / metabolism*
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • Serine / genetics
  • Serine / metabolism
  • Signal Transduction


  • Interleukin-2
  • NF-kappa B
  • Proto-Oncogene Proteins c-rel
  • Serine
  • Interferon-gamma
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Acetylglucosamine