Phosphorylation of NF-kappaB p65 at Ser468 controls its COMMD1-dependent ubiquitination and target gene-specific proteasomal elimination.
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.
Mesh Terms:
Animals, Cells, Cultured, Chromatin Immunoprecipitation, Interleukin-1, Lipopolysaccharides, Mice, Oligonucleotide Array Sequence Analysis, Phosphorylation, Promoter Regions, Genetic, Proteasome Endopeptidase Complex, Proteins, Transcription Factor RelA, Tumor Necrosis Factor-alpha, Ubiquitination
Animals, Cells, Cultured, Chromatin Immunoprecipitation, Interleukin-1, Lipopolysaccharides, Mice, Oligonucleotide Array Sequence Analysis, Phosphorylation, Promoter Regions, Genetic, Proteasome Endopeptidase Complex, Proteins, Transcription Factor RelA, Tumor Necrosis Factor-alpha, Ubiquitination
EMBO Rep.
Date: Apr. 01, 2009
PubMed ID: 19270718
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