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Review
. 2010 Sep;22(9):1282-90.
doi: 10.1016/j.cellsig.2010.03.017. Epub 2010 Apr 2.

Posttranslational modifications of NF-kappaB: another layer of regulation for NF-kappaB signaling pathway

Bo Huang  1 , Xiao-Dong Yang, Acacia Lamb, Lin-Feng Chen
Affiliations
Review

Posttranslational modifications of NF-kappaB: another layer of regulation for NF-kappaB signaling pathway

Bo Huang et al. Cell Signal. 2010 Sep.

Abstract

The eukaryotic transcription factor NF-kappaB regulates a wide range of host genes that control the inflammatory and immune responses, programmed cell death, cell proliferation and differentiation. The activation of NF-kappaB is tightly controlled both in the cytoplasm and in the nucleus. While the upstream cytoplasmic regulatory events for the activation of NF-kappaB are well studied, much less is known about the nuclear regulation of NF-kappaB. Emerging evidence suggests that NF-kappaB undergoes a variety of posttranslational modifications, and that these modifications play a key role in determining the duration and strength of NF-kappaB nuclear activity as well as its transcriptional output. Here we summarize the recent advances in our understanding of the posttranslational modifications of NF-kappaB, the interplay between the various modifications, and the physiological relevance of these modifications.

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Figures

Fig. 1
Fig. 1
Posttranslational modifications of RelA by phosphorylation, acetylation and methylation. (A) Regulation of RelA phosphorylation by various kinases and phosphatases. Schematic representation shows seven serine phosphorylation sites and three threonine phosphorylation sites identified in RelA. Most of the sites are located in the Rel homology domain (RHD) and the transactivation domains (TAD1 and TAD2). Several sites are phosphorylated by more than one kinase and some kinases phosphorylate numerous sites. The kinases for S205, S281, T254 and T435 are unknown right now. Three phosphatases have been shown to dephosphorylate RelA. (B) Reversible acetylation of RelA. RelA is acetylated by p300/CBP or PCAF at multiple lysines. Lysines 218, 221, 310, 314 and 315 are acetylated by p300/CBP, whereas lysines 122 and 123 are acetylated by both p300/CBP and PCAF. These acetylated sites are selectively deacetylated by HDAC1, HDAC3 or SIRT1, respectively. (C) Regulation of RelA by reversible lysine methylation. NSD1 monomethylates K218 and dimethylates K221; these methylated lysines are demethylated by FBXL11. Set9 monomethylates K37 and K314 and K315. Whether Set9-mediated methylation of K37, K314 and K315 is subject to demethylation is not known.
Fig. 2
Fig. 2
Interplays between various posttranslational modifications. Schematic models for the interplays between different modifications. (A) Phosphorylation enhances the acetylation of RelA. Stimulus-coupled phosphorylation of S276 or S536 leads to more effective recruitment of p300 and displacement of HDACs (1), which in turn mediates the acetylation of K310 (2). Phosphorylated and acetylated forms of RelA can transcribe NF-κB-dependent genes (3). (B) Acetylation of K310 inhibits RelA methylation at K314 and K315. p300-mediated acetylation of K310 inhibits the binding of Set9 to RelA, thereby impairing the Set9-mediated methylation of K314 and K315 (1). Deacetylation of RelA by SIRT1 (2) facilitates the recruitment of Set9 to RelA and consequently leads to the methylation of K314 and K315 (3) and the termination of NF-κB activation (4). (C) Phosphorylation of S468 stimulates the ubiquitination of RelA. IKKs-mediated phosphorylation of S468 (1) facilitates the binding of the COMMD1-containing ECS E3 ligase complex for the ubiquitination (2) and subsequent degradation and termination of NF-κB (3). (D) Methylation of RelA triggers the ubiquitination and degradation of NF-κB. Set9-mediated methylation of K314 and K315 (1) might create a docking site for the recruitment of an unknown E3 ligase for the ubiquitination (2) and subsequent degradation and termination of NF-κB (3).
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