期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2010
卷号：107
期号：1
页码：46-51
DOI：10.1073/pnas.0912493107
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：NF-{kappa}B, a central coordinator of immune and inflammatory responses, must be tightly regulated. We describe a NF-{kappa}B 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-{kappa}B activity, and a high level of NSD1 activates NF-{kappa}B and reverses the inhibitory effect of FBXL11, whereas reduced expression of NSD1 decreases NF-{kappa}B activation. The targets are K218 and K221 of p65, which are methylated in cells with activated NF-{kappa}B. 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-{kappa}B, revealing a negative regulatory feedback loop. We conclude that reversible lysine methylation of NF-{kappa}B is an important element in the complex regulation of this key transcription factor.
