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首页> 外文期刊>Molecular and Cellular Biology >Two Coordinated Mechanisms Underlie Tumor Necrosis Factor Alpha-Induced Immediate and Delayed IκB Kinase Activation
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Two Coordinated Mechanisms Underlie Tumor Necrosis Factor Alpha-Induced Immediate and Delayed IκB Kinase Activation

机译：肿瘤坏死因子α诱导的立即和延迟的IκB激酶激活的两个协调的机制。

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Tumor necrosis factor alpha (TNF-α)-induced NF-κB activation has been believed to depend on TRAF2- and cIAP1-mediated RIP1 ubiquitination. However, recent findings have challenged the notion that these proteins play essential roles in NF-κB activation. Here, by assessing the kinetics and amplitude of IκB kinase (IKK) activation, we report that TNF-α-induced immediate and robust activation of IKK requires K63-linked and linearly linked ubiquitination of RIP1 and that in the absence of RIP1 expression, TRAF2 and cIAP1 cooperatively induce delayed IKK activation by recruiting LUBAC to TNFR1. Knockdown of HOIP (a component of LUBAC) in RIP1-deficient cells completely impairs the recruitment and activation of IKK but does not affect K63-linked ubiquitination of TRAF2 and recruitment of TAK1 to TNFR1, suggesting that the K63-linked ubiquitin chain is not capable of recruiting IKK in vivo. We also demonstrate that TRAF2 and cIAP1 together, but not either one alone, directly catalyze linearly linked ubiquitination of RIP1. Importantly, in embryonic hepatocytes, TNF-α activates NF-κB through a RIP1-independent pathway. Thus, our findings clarify molecular details of this important signaling mechanism by providing evidence for the existence of two phases of IKK activation: the immediate phase, induced by TRAF2/cIAP1-mediated ubiquitination of RIP1, and the delayed phase, activated by TRAF2/cIAP1-dependent recruitment of LUBAC.
机译：肿瘤坏死因子α（TNF-α）诱导的NF-κB活化被认为取决于TRAF2和cIAP1介导的RIP1泛素化。但是，最近的发现挑战了这些蛋白质在NF-κB激活中起重要作用的观念。在这里，通过评估IκB激酶（IKK）激活的动力学和振幅，我们报道TNF-α诱导的IKK的即时和强大激活需要RIP1的K63连接和线性连接的泛素化，而在没有RIP1表达，TRAF2的情况下cIAP1和cIAP1通过将LUBAC募集到TNFR1来协同诱导IKK激活延迟。在RIP1缺陷细胞中敲低HOIP（LUBAC的一个组成部分）完全损害了IKK的募集和激活，但不影响TRAF2的K63连接泛素化和TAK1向TNFR1的募集，这表明K63连接的泛素链不起作用在体内募集IKK 。我们还证明了TRAF2和cIAP1在一起，而不是单独一个，直接催化RIP1的线性连接的泛素化。重要的是，在胚胎肝细胞中，TNF-α通过不依赖RIP1的途径激活NF-κB。因此，我们的发现通过提供IKK激活两个阶段的存在的证据来阐明这一重要信号传导机制的分子细节：由TRAF2 / cIAP1介导的RIP1泛化诱导的直接阶段，由TRAF2 / cIAP1激活的延迟阶段依赖的LUBAC招聘。

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