ReviewPosttranslational modifications of NF-κB: Another layer of regulation for NF-κB signaling pathway
Introduction
The eukaryotic transcription factor NF-κB/Rel family proteins regulate a wide range of host genes that govern the inflammatory and immune responses in mammals and play a critical role in controlling programmed cell death, cell proliferation and differentiation. In mammals, the NF-κB/Rel family consists of seven proteins, including RelA/p65, c-Rel, RelB, p100, p52, p105 and p50 [1], [2]. Each protein contains a Rel homology domain (RHD) within the N-terminus and can form homo- or heterodimers through the RHD [1], [2].
The prototypical NF-κB is a heterodimer of p50 and RelA. In unstimulated cells, NF-κB is sequestered in the cytoplasm by its association with an inhibitor protein, IκBα [1], [2]. NF-κB is activated by a variety of stimuli, including various proinflammatory cytokines, T- and B-cell receptor signals, and viral and bacterial products. Stimulation of the cells by these agonists leads to the activation of an IκB kinase complex of IκB kinases 1 and 2 (IKK1 and 2, also known as IKKα and IKKβ, respectively) and the non-catalytic NEMO subunit [3]. Activated IKKs then phosphorylate IκBα at serines-32 and -36, inducing its rapid ubiquitination and its degradation in the 26S proteasome [4]. The free NF-κB heterodimer rapidly translocates to the nucleus where it binds to the κB enhancer and stimulates gene expression through the transcriptional activation domain (TAD) of RelA [5]. NF-κB activates hundreds of genes involved in different biological processes including inflammation, proliferation and cell survival.
Many factors have been discovered to contribute to the transcriptional activation of NF-κB target genes, including the binding of different homo- or heterodimers of NF-κB to the cognate κB sites, the recruitment of various basal transcriptional factors and coactivators to the promoters, and the modifications of the histone tails around the promoters of NF-κB target genes [6]. Recent studies indicate that posttranslational modifications of NF-κB, especially of the RelA subunit, play a critical role in fine-tuning the transcriptional activity of NF-κB, adding another important layer of complexity to the transcriptional regulation of NF-κB. In the present review, we will focus on the posttranslational modifications of the RelA subunit of NF-κB, the regulation of these modifications, and the functions of these modifications in the NF-κB-mediated inflammatory response and cancer. Posttranslational modifications of other NF-κB members may be found in other recent reviews [6], [7], [8].
Section snippets
Phosphorylation of RelA
A role for phosphorylation of RelA in the regulation of NF-κB activity has long been suggested [9]. Accordingly, many kinases and phosphorylation sites including seven serines and three threonines have been identified (Fig. 1A). RelA can be phosphorylated both in the cytoplasm and in the nucleus in response to a variety of stimuli. Most of the phosphorylation sites are within the N-terminal RHD and the C-terminal transcriptional activation domains. Phosphorylation of these sites results in
Interplay between various posttranslational modifications
The interplay between different posttranslational modifications has been identified for histone and non-histone proteins, with one modification either enhancing or inhibiting another modification [74], [75]. The cross-talk between modifications together with the distinct combinations of covalent modifications form the basis of the “histone code” and probably the “protein code” hypothesis [76], [77]. RelA undergoes numerous posttranslational modifications, and there are many different interplays
Physiological relevance of posttranslational modifications
Although many of the above mentioned studies using biochemical and molecular approaches have demonstrated that various posttranslational modifications of RelA regulate distinct biological functions, especially the transcriptional activation of NF-κB, the physiological significance of these modifications is not well understood and is still being uncovered. Nevertheless, a growing number of studies have linked various posttranslational modifications to a variety of disease conditions, especially
Conclusions and future prospective
In the last several years, increasing numbers of studies demonstrate that posttranslational modifications of RelA in response to different stimuli differentially regulate the functions of NF-κB. In addition to fine-tuning the transcriptional activity of NF-κB, these various posttranslational modifications of RelA also contribute to NF-κB target gene specificity [6], adding another level of complexity to the regulation of NF-κB transcriptional activation.
Posttranslational modifications of
Acknowledgement
Due to space constraints, we were not able to cite all the important original work in this field, and apologize to those authors whose work we did not cite. This work is supported by Indirect Cost Recovery provided by the University of Illinois at Urbana-Champaign and by NIH grant DK-085158 to LF Chen.
References (100)
- et al.
Cell
(2002) - et al.
Cell
(1996) - et al.
Cell
(1997) - et al.
Cell. Signal.
(2007) - et al.
Mol. Cell
(1998) - et al.
J. Biol. Chem.
(1999) - et al.
J. Biol. Chem.
(2006) - et al.
J. Biol. Chem.
(2004) - et al.
J. Biol. Chem.
(2004) - et al.
J. Biol. Chem.
(2006)
J. Biol. Chem.
J. Biol. Chem.
J. Biol. Chem.
J. Biol. Chem.
J. Biol. Chem.
J. Biol. Chem.
Mol. Cell
J. Biol. Chem.
Curr. Opin. Cell Biol.
Mol. Cell
J. Biol. Chem.
Mol. Cell
Cell
Biochem. Biophys. Res. Commun.
Cell. Signal.
J. Biol. Chem.
Cancer Cell
Immunity
Cell Host. Microbe
Cancer Cell
Blood
Curr. Opin. Cell Biol.
Annu. Rev. Immunol.
Annu. Rev. Immunol.
Oncogene
Annu. Rev. Immunol.
Nat. Rev. Mol. Cell Biol.
FASEB J.
Oncogene
EMBO J.
EMBO J.
PLoS One
J. Immunol.
Mol. Cell. Biol.
Genes Dev.
Cell Death. Differ.
EMBO Rep.
Mol. Cell. Biol.
Mol. Cell. Biol.
FASEB J.
Cited by (261)
Remote preconditioning combined with nebulized budesonide alleviate lipopolysaccharide induced acute lung injury via regulating HO-1 and NF-κB in rats
2023, Pulmonary Pharmacology and TherapeuticsmiR-582-5p targets Skp1 and regulates NF-κB signaling-mediated inflammation
2023, Archives of Biochemistry and BiophysicsEpigenetic biomarkers: Where are we in cancer therapy
2023, Epigenetics in Human Disease, Third Edition
- 1
These authors contributed equally to this work.