NF-κB is a transcription factor that plays a key role in regulating cellular responses to stimuli such as stress and bacterial and viral infections. In un-stimulated cells, NF-κB dimers are sequestered in the cytoplasm by inhibitors known as IκBs (inhibitors of κB) which mask the nuclear localization signals of NF-κB. When the cell is stimulated, IκB proteins are degraded and the NF-κB complex is free to enter the nucleus where it can activate gene expression. The activation of particular genes by NF-κB then leads to a physiological response such as inflammation, an immune response, cell survival or cell proliferation. Once in the nucleus, NF-κB also turns on expression of IκBs, thus forming a feedback loop which regulates activity. Inappropriately regulated NF-κB has been linked to many different types of tumour as well as to inflammatory diseases.
Recent studies have shown that degradation of NF-κB in the nucleus provides an alternative mechanism for regulating its activity and researchers at the University of Illinois have now shown how this process is controlled. They found that TNF-α stimulates methylation of the RelA subunit of NF-κB by lysine methyltransferase Set9 at lysine residues 314 and 315 both in vitro and in vivo. Methylation of RelA inactivates NF-κB by inducing proteasome-mediated degradation of promoter-associated RelA. Depletion of Set9 by siRNA or mutation of the RelA methylation sites was shown to prolong DNA binding of NF-κB and enhance TNF-α-induced expression of NF-κB target genes.
The study, which is published in the journal EMBO, reveals methylation of the RelA subunit of NF-κB as a novel mechanism regulating the turnover of NF-κB and controlling the NF-κB-mediated inflammatory response. The ability to inhibit NF-κB signalling could have applications in the treatment of both cancer and inflammatory diseases.
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