Regulation of NF-κB by NSD1/FBXL11-dependent reversible lysine methylation of p65

Tao Lu, Mark W. Jackson, Benlian Wang, Maojing Yang, Mark R. Chance, Masaru Miyagi, Andrei V. Gudkov, George R. Stark

Research output: Contribution to journalArticle

165 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)46-51
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number1
DOIs
StatePublished - 2010
Externally publishedYes

Fingerprint

Methylation
Lysine
HT29 Cells
Cytoplasmic and Nuclear Receptors
Small Interfering RNA
Genes
Transcription Factors
Embryonic Structures
Fibroblasts
leucine-rich repeat proteins
Phenotype
Growth
Neoplasms

Keywords

  • Demethylase
  • Histone
  • Mass spectrometry
  • Methylase
  • Transcription factor

ASJC Scopus subject areas

  • General

Cite this

Regulation of NF-κB by NSD1/FBXL11-dependent reversible lysine methylation of p65. / Lu, Tao; Jackson, Mark W.; Wang, Benlian; Yang, Maojing; Chance, Mark R.; Miyagi, Masaru; Gudkov, Andrei V.; Stark, George R.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 1, 2010, p. 46-51.

Research output: Contribution to journalArticle

Lu, Tao ; Jackson, Mark W. ; Wang, Benlian ; Yang, Maojing ; Chance, Mark R. ; Miyagi, Masaru ; Gudkov, Andrei V. ; Stark, George R. / Regulation of NF-κB by NSD1/FBXL11-dependent reversible lysine methylation of p65. In: Proceedings of the National Academy of Sciences of the United States of America. 2010 ; Vol. 107, No. 1. pp. 46-51.
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