Nuclear accumulation of cRel following C-terminal phosphorylation by TBK1/IKK epsilon.
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.
Harris
Jennifer
J
Terry Fox Molecular Oncology Group, Lady Davis Institute for Medical Research, 3755 chemin de la Cote Sainte Catherine, Montréal, Québec, Canada.
Olière
Stéphanie
S
Sharma
Sonia
S
Sun
Qiang
Q
Lin
Rongtuan
R
Hiscott
John
J
Grandvaux
Nathalie
N
D000595:Amino Acid Sequence; D002460:Cell Line; D002467:Cell Nucleus / Q000201:enzymology / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000502:physiology*; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D017434:Protein Structure, Tertiary; D020569:Proto-Oncogene Proteins c-rel / Q000378:metabolism*
D016328:NF-kappa B; D020569:Proto-Oncogene Proteins c-rel; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human; D051550:I-kappa B Kinase; C496565:IKBKE protein, human