title: Regulation of NF-κB activity by competition between RelA acetylation and ubiquitination.
abstract: The nuclear factor (NF)-κB transcription factor has essential roles in inflammation and oncogenesis. Its ubiquitous RelA subunit is regulated by several post-translational modifications, including phosphorylation, ubiquitination and acetylation. Ubiquitination promotes the termination of RelA-dependent transcription, but its regulation is incompletely understood. Through mass spectrometry analysis of ubiquitinated RelA, we identified seven lysines that were attached to degradative and non-degradative forms of polyubiquitin. Interestingly, lysines targeted for acetylation were among the residues identified as ubiquitin acceptor sites. Mutation of these particular sites resulted in decreased polyubiquitination. Acetylation and ubiquitination were found to inhibit each other, consistent with their use of overlapping sites. Reconstitution of rela(-/-) fibroblasts with wild-type and mutant forms of RelA revealed that modifications at these residues can have activating and inhibitory functions depending on the target gene context. Altogether, this study elucidates that ubiquitination and acetylation can modulate each other and regulate nuclear NF-κB function in a gene-specific manner.
authors.affiliation: Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75230-9151, USA.
authors.forename: H
authors.initials: H
authors.lastname: Li
authors.forename: T
authors.initials: T
authors.lastname: Wittwer
authors.forename: A
authors.initials: A
authors.lastname: Weber
authors.forename: H
authors.initials: H
authors.lastname: Schneider
authors.forename: R
authors.initials: R
authors.lastname: Moreno
authors.forename: G N
authors.initials: GN
authors.lastname: Maine
authors.forename: M
authors.initials: M
authors.lastname: Kracht
authors.forename: M L
authors.initials: ML
authors.lastname: Schmitz
authors.forename: E
authors.initials: E
authors.lastname: Burstein
mesh_terms: D000107:Acetylation; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D020869:Gene Expression Profiling; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C090509:Icam1 protein, mouse; D016328:NF-kappa B; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D025801:Ubiquitin; D018799:Intercellular Adhesion Molecule-1; D008239:Lysine