Harris Jennifer, Olière Stéphanie, Sharma Sonia, Sun Qiang, Lin Rongtuan, Hiscott John, Grandvaux Nathalie
Terry Fox Molecular Oncology Group, Lady Davis Institute for Medical Research, 3755 chemin de la Cote Sainte Catherine, Montréal, Québec, Canada.
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.
核因子-κB（NF-κB）转录因子是免疫调节、细胞周期及发育基因调控的关键调节因子。NF-κB的活性主要通过IκB激酶（IKK）复合体IKKαβγ对IκB的磷酸化作用来调节，从而导致蛋白酶体介导的IκB降解、NF-κB二聚体的核转位、DNA结合及基因诱导。此外，已经证实NF-κB p65和cRel亚基存在涉及C末端磷酸化的直接翻译后修饰。非经典的IKK相关同源物，即肿瘤坏死因子受体相关因子家族成员相关的NF-κB激活剂（TANK）结合激酶（TBK）1和IKKε，也被认为在NF-κB调节中发挥作用，但其功能仍不清楚。最近有报道称，TBK1和IKKε通过直接磷酸化干扰素调节因子-3和-7转录因子，成为干扰素基因激活的关键调节因子。在本研究中，我们试图确定IKKε和TBK1是否可通过磷酸化调节cRel的活性。TBK1和IKKε在体外和体内均可直接磷酸化cRel的C末端结构域，并独立于经典的IκB/IKK途径调节cRel的核积累。IκBα的降解不受影响，相反，IKKε介导的cRel磷酸化导致IκBα-cRel复合体解离。这些结果揭示了cRel调节中一个以前未被认识的方面，即由IKKε/TBK1直接磷酸化所控制。
