'American Association for the Advancement of Science (AAAS)'
Abstract
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 b-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 IkBa) 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