Hyper-O-GlcNAcylation activates NF-{kappa}B signaling through interplay with phosphorylation and acetylation [Signal Transduction]

O-GlcNAcylation is the covalent addition of an O-linked β-N-acetylglucosamine (O-GlcNAc) sugar moiety to hydroxyl groups of serine/threonine residues of cytosolic and nuclear proteins. O-GlcNAcylation, analogous to phosphorylation, plays critical roles in gene expression through direct modification of transcription factors such as NF-κB. Aberrantly increased NF-κB O-GlcNAcylation has been linked to NF-κB constitutive activation and cancer development. Therefore, it is of a great biological and clinical significance to dissect the molecular mechanisms that tune NF-κB activity. Recently, we and others have shown that O-GlcNAcylation affects the phosphorylation and acetylation of NF-κB subunit p65/RelA. However, the mechanism of how O-GlcNAcylation activates NF-κB signaling through phosphorylation and acetylation is not fully understood. In this study, we mapped O-GlcNAcylation sites of p65 at T305, S319, S337, T352, and S374. O-GlcNAcylation of p65 at T305 and S319 increased CBP/p300-dependent activating acetylation of p65 at K310, contributing to NF-κB transcriptional activation. Moreover, elevation of O-GlcNAcylation by overexpression of OGT increased the expression of p300, IKKα and IKKβ and promoted IKK-mediated activating phosphorylation of p65 at S536, contributing to NF-κB activation. In addition, we also identified phosphorylation of p65 at T308, which impaired the O-GlcNAcylation of p65 at T305. These results indicate mechanisms through which both non-pathological and oncogenic O-GlcNAcylation regulates NF-κB signaling through interplay with phosphorylation and acetylation.

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