Hyper-O-GlcNAcylation activates nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) signaling through interplay with phosphorylation and acetylation
| Autor: | Zhiyuan Ma, Keith Vosseller, Robert J. Chalkley |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Biochemistry & Molecular Biology Biology Medical and Health Sciences Biochemistry Phosphorylation cascade Serine Mice 03 medical and health sciences O-GlcNAcylation 0302 clinical medicine Animals Humans 2.1 Biological and endogenous factors p300-CBP Transcription Factors NF-kappaB Aetiology Nuclear protein Threonine Enhancer Molecular Biology Transcription factor phosphorylation E1A-binding protein p300 Transcription Factor RelA Acetylation Cell Biology Biological Sciences I-kappa B Kinase HEK293 Cells 030104 developmental biology Chemical Sciences Phosphorylation 030217 neurology & neurosurgery Signal Transduction |
| Zdroj: | The Journal of biological chemistry, vol 292, iss 22 |
| ISSN: | 0021-9258 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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