Phosphorylation of NF-kappaB p65 at Ser468 controls its COMMD1-dependent ubiquitination and target gene-specific proteasomal elimination

EMBO Rep. 2009 Apr;10(4):381-6. doi: 10.1038/embor.2009.10. Epub 2009 Mar 6.


The nuclear factor-kappaB (NF-kappaB) transcription factor system is a crucial component that controls several important biological functions, thus raising the need for mechanisms that ensure the correct termination of its activity. Here, we identify a new phosphorylation/ubiquitination switch in the NF-kappaB network that controls the stability of the transactivating p65 subunit. Tumour necrosis factor-induced phosphorylation of p65 at Ser468 allows binding of COMMD1 and cullin 2, components of a multimeric ubiquitin ligase complex mediating p65 ubiquitination. Mutation of p65 at Ser468 largely prevents p65 ubiquitination and proteasomal degradation. Inducible p65 elimination is restricted to a subset of NF-kappaB target genes such as Icam1. Accordingly, chromatin immunoprecipitation experiments reveal the selective recruitment of Ser468-phosphorylated p65 and COMMD1 to the Icam1 promoter. Phosphorylation of p65 at Ser468 leads to ubiquitin/proteasome-dependent removal of chromatin-bound p65, thus contributing to the selective termination of NF-kappaB-dependent gene expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Cells, Cultured
  • Chromatin Immunoprecipitation
  • Interleukin-1 / pharmacology
  • Lipopolysaccharides / pharmacology
  • Mice
  • Oligonucleotide Array Sequence Analysis
  • Phosphorylation / drug effects
  • Promoter Regions, Genetic / genetics
  • Proteasome Endopeptidase Complex / metabolism*
  • Proteins / metabolism*
  • Transcription Factor RelA / metabolism*
  • Tumor Necrosis Factor-alpha / pharmacology
  • Ubiquitination / drug effects


  • Adaptor Proteins, Signal Transducing
  • Commd1 protein, mouse
  • Interleukin-1
  • Lipopolysaccharides
  • Proteins
  • Rela protein, mouse
  • Transcription Factor RelA
  • Tumor Necrosis Factor-alpha
  • Proteasome Endopeptidase Complex