An unexpected twist to the activation of IKKβ: TAK1 primes IKKβ for activation by autophosphorylation.
An unexpected twist to the activation of IKKβ: TAK1 primes IKKβ for activation by autophosphorylation.
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DOI：
10.1042/bj20140444
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发表时间：
2014-08-01
期刊：
影响因子：
--
通讯作者：
Cohen P
中科院分区：
文献类型：
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作者：
Zhang J;Clark K;Lawrence T;Peggie MW;Cohen P
IKKβ {IκB [NF-κB（核因子κB）抑制剂]激酶β}是激活转录因子NF-κB所必需的，但IKKβ本身在体内是如何被激活的尚不清楚。在一些报道中发现它需要一个或多个“上游”蛋白激酶磷酸化，但在其他报道中则需要自磷酸化。在本研究中，我们通过证明IL-1诱导的IKKβ激活（白细胞介素-1）或TNF在胚胎成纤维细胞中的肿瘤坏死因子（tumor necrosis factor），或通过激活巨噬细胞中Toll样受体的配体，需要两个不同的磷酸化事件：首先，TAK 1 [TGFβ（转化生长因子β）激活的激酶-1]催化Ser 177的磷酸化，其次，IKKβ催化Ser 181的自身磷酸化。TK 1对Ser 177的磷酸化是随后Ser 181自磷酸化所需的引发事件，这使得IKKβ能够磷酸化外源底物。我们还提供了遗传学证据，表明IL-1刺激的LUBAC（线性遍在蛋白链组装复合物）催化的线性遍在蛋白链的形成及其与经典IKK复合物的NEMO（NF-κB必需调节剂）组分的相互作用允许TK 1催化的IKKβ在Ser 177和IKKα在Ser 176的引发磷酸化。这些发现可能对其他蛋白激酶的激活具有普遍意义。我们已经发现了一种控制免疫系统的关键酶是如何在细菌和病毒感染期间被打开的。它被称为IKKβ，它触发了许多对抗这些病原体所需的蛋白质的产生。
IKKβ {IκB [inhibitor of NF-κB (nuclear factor κB)] kinase β} is required to activate the transcription factor NF-κB, but how IKKβ itself is activated in vivo is still unclear. It was found to require phosphorylation by one or more ‘upstream’ protein kinases in some reports, but by autophosphorylation in others. In the present study, we resolve this contro-versy by demonstrating that the activation of IKKβ induced by IL-1 (interleukin-1) or TNF (tumour necrosis factor) in embryonic fibroblasts, or by ligands that activate Toll-like receptors in macrophages, requires two distinct phosphorylation events: first, the TAK1 [TGFβ (transforming growth factor β)-activated kinase-1]-catalysed phosphorylation of Ser177 and, secondly, the IKKβ-catalysed autophosphorylation of Ser181. The phosphorylation of Ser177 by TAK1 is a priming event required for the subsequent autophosphorylation of Ser181, which enables IKKβ to phosphorylate exogenous substrates. We also provide genetic evidence which indicates that the IL-1-stimulated, LUBAC (linear ubiquitin chain assembly complex)-catalysed formation of linear ubiquitin chains and their interaction with the NEMO (NF-κB essential modulator) component of the canonical IKK complex permits the TAK1-catalysed priming phosphorylation of IKKβ at Ser177 and IKKα at Ser176. These findings may be of general significance for the activation of other protein kinases. We have discovered how a key enzyme that controls the immune system is switched on during infection by bacteria and viruses. Known by the acronym IKKβ, it triggers the production of many proteins that are needed to combat these pathogens.