Activation of the Transcriptional Function of the NF-κB Protein c-Rel by O-GlcNAc Glycosylation

摘要

The transcription factor nuclear factor κB (NF-κB) rapidly reprograms gene expression in response toudvarious stimuli, and its activity is regulated by several posttranslational modifications, including phosphorylation,udmethylation, and acetylation. The addition of O-linked b-N-acetylglucosamine (a processudknown as O-GlcNAcylation) is an abundant posttranslational modification that is enhanced in conditionsudsuch as hyperglycemia and cellular stress. We report that the NF-κB subunit c-Rel is modified and activatedudby O-GlcNAcylation. We identified serine 350 as the site of O-GlcNAcylation, which was required forudthe DNA binding and transactivation functions of c-Rel. Blocking the O-GlcNAcylation of this residue abrogatedudc-Rel–mediated expression of the cytokine-encoding genes IL2, IFNG, and CSF2 in response to Tudcell receptor (TCR) activation, whereas increasing the extent of O-GlcNAcylation of cellular proteinsudenhanced the expression of these genes. TCR- or tumor necrosis factor (TNF)–induced expression of otherudNF-κB target genes, such as NFKBIA (which encodes IkBa) and TNFAIP3 (which encodes A20),udoccurred independently of the O-GlcNAcylation of c-Rel. Our findings suggest a stimulus-specific roleudfor hyperglycemia-induced O-GlcNAcylation of c-Rel in promoting T cell–mediated autoimmunity inudconditions such as type 1 diabetes by enhancing the production of T helper cell cytokines.