Regulation of NF-B activity by competition between RelA acetylation and ubiquitination

H. Li, T. Wittwer, A. Weber, H. Schneider, R. Moreno, G. N. Maine, M. Kracht, M. L. Schmitz, E. Burstein

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

The nuclear factor (NF)-B 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.

Original languageEnglish (US)
Pages (from-to)611-623
Number of pages13
JournalOncogene
Volume31
Issue number5
DOIs
StatePublished - Feb 2 2012

Keywords

  • NF-κB
  • RelA
  • acetylation
  • p65
  • transcription
  • ubiquitination

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Li, H., Wittwer, T., Weber, A., Schneider, H., Moreno, R., Maine, G. N., Kracht, M., Schmitz, M. L., & Burstein, E. (2012). Regulation of NF-B activity by competition between RelA acetylation and ubiquitination. Oncogene, 31(5), 611-623. https://doi.org/10.1038/onc.2011.253