Phosphorylation and ubiquitination of the IκB kinase complex by two distinct signaling pathways
Phosphorylation and ubiquitination of the IκB kinase complex by two distinct signaling pathways
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DOI：
10.1038/sj.emboj.7601622
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发表时间：
2007-04-04
期刊：
影响因子：
11.4
通讯作者：
Lin, Xin
中科院分区：
文献类型：
--
作者：
Shambharkar, Prashant B.;Blonska, Marzenna;Lin, Xin
I κ B激酶（IKK）复合物作为各种刺激激活NF-κ B的主要调节因子。它包含两个催化亚基IKK α和IKK β，以及一个调节亚基IKK γ/NEMO。IKK复合物的活化依赖于IKK α/β在其活化环的磷酸化和K63连接的NEMO泛素化。然而，这些诱导性修饰发生的分子机制仍然不确定。在这里，我们证明了CARMA 1，一个关键的支架分子，是必不可少的调节NEMO泛素化T细胞受体（TCR）刺激。然而，IKK α/β激活环的磷酸化不依赖于CARMA 1或NEMO泛素化。此外，我们提供的证据表明，TAK 1以不依赖于CARMA 1的方式被激活并募集到突触，并介导IKK α/β磷酸化。因此，我们的研究提供了生物化学和遗传学证据，IKK α/β的磷酸化和NEMO的泛素化在TCR刺激后由两种不同的途径调节。
The I kappa B kinase (IKK) complex serves as the master regulator for the activation of NF-kappa B by various stimuli. It contains two catalytic subunits, IKK alpha and IKK beta, and a regulatory subunit, IKK gamma/NEMO. The activation of IKK complex is dependent on the phosphorylation of IKK alpha/beta at its activation loop and the K63-linked ubiquitination of NEMO. However, the molecular mechanism by which these inducible modifications occur remains undefined. Here, we demonstrate that CARMA1, a key scaffold molecule, is essential to regulate NEMO ubiquitination upon T-cell receptor (TCR) stimulation. However, the phosphorylation of IKK alpha/beta activation loop is independent of CARMA1 or NEMO ubiquitination. Further, we provide evidence that TAK1 is activated and recruited to the synapses in a CARMA1-independent manner and mediate IKK alpha/beta phosphorylation. Thus, our study provides the biochemical and genetic evidence that phosphorylation of IKK alpha/beta and ubiquitination of NEMO are regulated by two distinct pathways upon TCR stimulation.