Hyper- O -GlcNAcylation activates nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) signaling through interplay with phosphorylation and acetylation.

Autor:	Ma Z; From the Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102 and zhiyuan.ma@dm.duke.edu., Chalkley RJ; the Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158., Vosseller K; From the Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102 and kvosseller@gmail.com.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2017 Jun 02; Vol. 292 (22), pp. 9150-9163. Date of Electronic Publication: 2017 Apr 17.
DOI:	10.1074/jbc.M116.766568
Abstrakt:	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 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-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 Ser-536, contributing to NF-κB 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-κB signaling through interplay with phosphorylation and acetylation. Competing Interests: The authors declare that they have no conflicts of interest with the contents of this article. (© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)
Databáze:	MEDLINE
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