title: Phosphorylation of NF-kappaB p65 at Ser468 controls its COMMD1-dependent ubiquitination and target gene-specific proteasomal elimination.
abstract: 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.
authors.affiliation: Institute of Biochemistry, Medical Faculty, Friedrichstrasse 24, Justus-Liebig-University, D-35392 Giessen, Germany.
authors.forename: Hui
authors.initials: H
authors.lastname: Geng
authors.forename: Tobias
authors.initials: T
authors.lastname: Wittwer
authors.forename: Oliver
authors.initials: O
authors.lastname: Dittrich-Breiholz
authors.forename: Michael
authors.initials: M
authors.lastname: Kracht
authors.forename: Michael Lienhard
authors.initials: ML
authors.lastname: Schmitz
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D007375:Interleukin-1 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C103799:Commd1 protein, mouse; D007375:Interleukin-1; D008070:Lipopolysaccharides; D011506:Proteins; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D046988:Proteasome Endopeptidase Complex