Regulation of NF-κB by NSD1/FBXL11-dependent reversible lysine methylation of p65
Open Access
- 29 December 2009
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 107 (1), 46-51
- https://doi.org/10.1073/pnas.0912493107
Abstract
NF-κB, a central coordinator of immune and inflammatory responses, must be tightly regulated. We describe a NF-κB regulatory pathway that is driven by reversible lysine methylation of the p65 subunit, carried out by a lysine methylase, the nuclear receptor–binding SET domain-containing protein 1 (NSD1), and a lysine demethylase, F-box and leucine-rich repeat protein 11 (FBXL11). Overexpression of FBXL11 inhibits NF-κB activity, and a high level of NSD1 activates NF-κB and reverses the inhibitory effect of FBXL11, whereas reduced expression of NSD1 decreases NF-κB activation. The targets are K218 and K221 of p65, which are methylated in cells with activated NF-κB. Overexpression of FBXL11 slowed the growth of HT29 cancer cells, whereas shRNA-mediated knockdown had the opposite effect, and these phenotypes were dependent on K218/K221 methylation. In mouse embryo fibroblasts, the activation of most p65-dependent genes relied on K218/K221 methylation. Importantly, expression of the FBXL11 gene is driven by NF-κB, revealing a negative regulatory feedback loop. We conclude that reversible lysine methylation of NF-κB is an important element in the complex regulation of this key transcription factor.Keywords
This publication has 31 references indexed in Scilit:
- Regulation of NF-κB activity through lysine monomethylation of p65Proceedings of the National Academy of Sciences, 2009
- Validation-based insertional mutagenesis identifies lysine demethylase FBXL11 as a negative regulator of NFκBProceedings of the National Academy of Sciences, 2009
- Negative regulation of NF-κB action by Set9-mediated lysine methylation of the RelA subunitThe EMBO Journal, 2009
- Functional relevance of novel p300-mediated lysine 314 and 315 acetylation of RelA/p65Nucleic Acids Research, 2008
- Methylation-Acetylation Interplay Activates p53 in Response to DNA DamageMolecular and Cellular Biology, 2007
- The Histone H3 Lysine-27 Demethylase Jmjd3 Links Inflammation to Inhibition of Polycomb-Mediated Gene SilencingCell, 2007
- Chromatin Modifications and Their FunctionCell, 2007
- Nuclear factor-κB in cancer development and progressionNature, 2006
- Good cop, bad cop: the different faces of NF-κBCell Death & Differentiation, 2006
- The language of covalent histone modificationsNature, 2000