Nuclear accumulation of cRel following C-terminal phosphorylation by TBK1/IKKε
Nuclear accumulation of cRel following C-terminal phosphorylation by TBK1/IKKε
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DOI：
10.4049/jimmunol.177.4.2527
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发表时间：
2006-08-15
影响因子：
4.4
通讯作者：
Grandvaux, Nathalie
中科院分区：
文献类型：
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作者：
Harris, Jennifer;Oliere, Stephanie;Grandvaux, Nathalie
NF-κ B转录因子是免疫调节、细胞周期和发育基因调控的关键调节因子。NF-κ B活性主要通过I κ B激酶（IKK）复合物IKK α β γ对I κ B的磷酸化调节，导致蛋白酶体介导的I κ B降解、NF-κ B二聚体的核转位、DNA结合和基因诱导。此外，已证实NF-κ B p65和cRel亚基的直接翻译后修饰涉及C-末端磷酸化。非经典IKK相关同源物，TNFR相关因子家族成员相关NF-κ B激活剂（TANK）结合激酶（TBK）1和IKK β，也被认为在NF-κ B调节中发挥作用，但其功能尚不清楚。TBK 1和IKK β最近被描述为通过直接磷酸化IFN调节因子-3和-7转录因子而激活IFN基因的重要调节因子。在本研究中，我们试图确定IKK β和TBK 1是否可以通过磷酸化调节cRel活性。TBK 1和IKK β在体外和体内直接磷酸化cRel的C-末端结构域，并调节cRel的核积聚，独立于经典的I κ B/IKK途径。I κ B α降解不受影响，但IKK ε介导的cRel磷酸化导致I κ B α-cRel复合物解离。这些结果说明了cRel调节的一个以前未被认识的方面，由直接IKK β/TBK 1磷酸化控制。
The NF-kappa B transcription factors are key regulators of immunomodulatory, cell cycle, and developmental gene regulation. NF-kappa B activity is mainly regulated through the phosphorylation of I kappa B by the I kappa B kinase (IKK) complex IKK alpha beta gamma, leading to proteasome-mediated degradation of I kappa B, nuclear translocation of NF-kappa B dimers, DNA binding, and gene induction. Additionally, direct posttranslational modifications of NF-kappa B p65 and cRel subunits involving C-terminal phosphorylation has been demonstrated. The noncanonical IKK-related homologs, TNFR-associated factor family member-associated NF-kappa B activator (TANK)-binding kinase (TBK)1 and IKK epsilon, are also thought to play a role in NF-kappa B regulation, but their functions remain unclear. TBK1 and IKK epsilon 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 epsilon and TBK1 could modulate cRel activity via phosphorylation. TBK1 and IKK epsilon directly phosphorylate the C-terminal domain of cRel in vitro and in vivo and regulate nuclear accumulation of cRel, independently of the classical I kappa B/IKK pathway. I kappa B alpha degradation is not affected, but rather IKK epsilon-mediated phosphorylation of cRel leads to dissociation of the I kappa B alpha-cRel complex. These results illustrate a previously unrecognized Aspect of cRel regulation, controlled by direct IKK epsilon/TBK1 phosphorylation.