NFκB activation is associated with its O-GlcNAcylation state under hyperglycemic conditions

The transcription factor NF kappa B is activated by phosphorylation and acetylation and plays important roles in inflammatory and immune responses in the cell. Additionally, posttranslational modification of the NF kappa B p65 subunit by O-linked N-acetylglucosamine (O-GlcNAc) has been reported, but the modification site of O-GlcNAc on NF kappa B p65 and its exact function have not been elucidated. In this work, we show that O-GlcNAcylation of NF kappa B p65 decreases binding to I kappa B alpha and increases transcriptional activity under hyperglycemic conditions. Also, we demonstrate that both Thr-322 and Thr-352 of NF kappa B p65 can be modified with O-GlcNAc, but modification on Thr-352, not Thr-322, is important for transcriptional activation. Our findings suggest that site-specific O-GlcNAcylation may be a reason why NF kappa B activity increases continuously under hyperglycemic conditions.