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1
Terry Fox Molecular Oncology Group, Lady Davis Institute for Medical Research, and Department of Microbiology & Immunology, Department of Medicine and Department of Oncology, McGill University, Montréal, Québec, Canada; and 
Department of Biochemistry, Centre de Recherche du CHUM, Faculty of Medicine, University of Montréal, Montréal H2X 1P1, Québec, Canada
The NF-
B transcription factors are key regulators of immunomodulatory, cell cycle, and developmental gene regulation. NF-B activity is mainly regulated through the phosphorylation of IB by the IB kinase (IKK) complex IKK
, leading to proteasome-mediated degradation of IB, nuclear translocation of NF-B dimers, DNA binding, and gene induction. Additionally, direct posttranslational modifications of NF-B p65 and cRel subunits involving C-terminal phosphorylation has been demonstrated. The noncanonical IKK-related homologs, TNFR-associated factor family member-associated NF-B activator (TANK)-binding kinase (TBK)1 and IKK
, are also thought to play a role in NF-B regulation, but their functions remain unclear. TBK1 and IKK 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 IKK and TBK1 could modulate cRel activity via phosphorylation. TBK1 and IKK directly phosphorylate the C-terminal domain of cRel in vitro and in vivo and regulate nuclear accumulation of cRel, independently of the classical IB/IKK pathway. IB degradation is not affected, but rather IKK-mediated phosphorylation of cRel leads to dissociation of the IB-cRel complex. These results illustrate a previously unrecognized aspect of cRel regulation, controlled by direct IKK/TBK1 phosphorylation.
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