Negative regulation of NF-kappaB action by Set9-mediated lysine methylation of the RelA subunit.


Journal Article

Proper regulation of NF-kappaB activity is critical to maintain and balance the inflammatory response. Inactivation of the NF-kappaB complex relies in part on the proteasome-mediated degradation of promoter-bound NF-kappaB, but the detailed molecular mechanism initiating this process remains elusive. Here, we show that the methylation of the RelA subunit of NF-kappaB has an important function in this process. Lysine methyltransferase Set9 physically associates with RelA in vitro and in vivo in response to TNF-alpha stimulation. Mutational and mass spectrometric analyses reveal that RelA is monomethylated by Set9 at lysine residues 314 and 315 in vitro and in vivo. Methylation of RelA inhibits NF-kappaB action by inducing the proteasome-mediated degradation of promoter-associated RelA. Depletion of Set9 by siRNA or mutation of the RelA methylation sites prolongs DNA binding of NF-kappaB and enhances TNF-alpha-induced expression of NF-kappaB target genes. Together, these findings unveil a novel mechanism by which methylation of RelA dictates the turnover of NF-kappaB and controls the NF-kappaB-mediated inflammatory response.

Full Text

Cited Authors

  • Yang, X-D; Huang, B; Li, M; Lamb, A; Kelleher, NL; Chen, L-F

Published Date

  • April 2009

Published In

Volume / Issue

  • 28 / 8

Start / End Page

  • 1055 - 1066

PubMed ID

  • 19262565

Pubmed Central ID

  • 19262565

Electronic International Standard Serial Number (EISSN)

  • 1460-2075

International Standard Serial Number (ISSN)

  • 0261-4189

Digital Object Identifier (DOI)

  • 10.1038/emboj.2009.55


  • eng