Nuclear accumulation of cRel following C-terminal phosphorylation by TBK1/IKK epsilon

J Immunol. 2006 Aug 15;177(4):2527-35. doi: 10.4049/jimmunol.177.4.2527.


The NF-kappaB transcription factors are key regulators of immunomodulatory, cell cycle, and developmental gene regulation. NF-kappaB activity is mainly regulated through the phosphorylation of IkappaB by the IkappaB kinase (IKK) complex IKKalphabetagamma, leading to proteasome-mediated degradation of IkappaB, nuclear translocation of NF-kappaB dimers, DNA binding, and gene induction. Additionally, direct posttranslational modifications of NF-kappaB p65 and cRel subunits involving C-terminal phosphorylation has been demonstrated. The noncanonical IKK-related homologs, TNFR-associated factor family member-associated NF-kappaB activator (TANK)-binding kinase (TBK)1 and IKKepsilon, are also thought to play a role in NF-kappaB regulation, but their functions remain unclear. TBK1 and IKKepsilon were recently described as essential regulators of IFN gene activation through direct phosphorylation of the IFN regulatory factor-3 and -7 transcription factors. In the present study, we sought to determine whether IKKepsilon and TBK1 could modulate cRel activity via phosphorylation. TBK1 and IKKepsilon directly phosphorylate the C-terminal domain of cRel in vitro and in vivo and regulate nuclear accumulation of cRel, independently of the classical IkappaB/IKK pathway. IkappaBalpha degradation is not affected, but rather IKKepsilon-mediated phosphorylation of cRel leads to dissociation of the IkappaBalpha-cRel complex. These results illustrate a previously unrecognized aspect of cRel regulation, controlled by direct IKKepsilon/TBK1 phosphorylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Cell Line
  • Cell Nucleus / enzymology
  • Cell Nucleus / metabolism*
  • HeLa Cells
  • Humans
  • I-kappa B Kinase / physiology*
  • Molecular Sequence Data
  • NF-kappa B / metabolism
  • Phosphorylation
  • Protein Serine-Threonine Kinases / physiology*
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-rel / metabolism*


  • NF-kappa B
  • Proto-Oncogene Proteins c-rel
  • Protein Serine-Threonine Kinases
  • TBK1 protein, human
  • I-kappa B Kinase
  • IKBKE protein, human