Hyper-O-GlcNAcylation activates nuclear factor ?-light-chain-enhancer of activated B cells (NF-?B) signaling through interplay with phosphorylation and acetylation.
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ABSTRACT: O-GlcNAcylation is the covalent addition of an O-linked ?-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-?B. Aberrantly increased NF-?B O-GlcNAcylation has been linked to NF-?B constitutive activation and cancer development. Therefore, it is of a great biological and clinical significance to dissect the molecular mechanisms that tune NF-?B activity. Recently, we and others have shown that O-GlcNAcylation affects the phosphorylation and acetylation of NF-?B subunit p65/RelA. However, the mechanism of how O-GlcNAcylation activates NF-?B signaling through phosphorylation and acetylation is not fully understood. In this study, we mapped O-GlcNAcylation sites of p65 at Thr-305, Ser-319, Ser-337, Thr-352, and Ser-374. O-GlcNAcylation of p65 at Thr-305 and Ser-319 increased CREB-binding protein (CBP)/p300-dependent activating acetylation of p65 at Lys-310, contributing to NF-?B transcriptional activation. Moreover, elevation of O-GlcNAcylation by overexpression of OGT increased the expression of p300, IKK?, and IKK? and promoted IKK-mediated activating phosphorylation of p65 at Ser-536, contributing to NF-?B activation. In addition, we also identified phosphorylation of p65 at Thr-308, which might impair the O-GlcNAcylation of p65 at Thr-305. These results indicate mechanisms through which both non-pathological and oncogenic O-GlcNAcylation regulate NF-?B signaling through interplay with phosphorylation and acetylation.
SUBMITTER: Ma Z
PROVIDER: S-EPMC5454098 | biostudies-literature | 2017 Jun
REPOSITORIES: biostudies-literature
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