Activation of IKK by TNFα requires site-specific ubiquitination of RIP1 and polyubiquitin binding by NEMO
Activation of IKK by TNFα requires site-specific ubiquitination of RIP1 and polyubiquitin binding by NEMO
复制标题
DOI：
10.1016/j.molcel.2006.03.026
复制
发表时间：
2006-04-21
期刊：
影响因子：
16
通讯作者：
Chen, ZJJ
中科院分区：
文献类型：
--
作者：
Ea, CK;Deng, L;Chen, ZJJ
受体相互作用蛋白激酶1 （RIP1）是肿瘤坏死因子α (TNF α)激活核因子κ B （nf - κ B）所必需的。在这里，我们提供的证据表明，TNF α诱导RIP1在Lys-377位点的多泛素化，并且这种多泛素化是激活ikappa B激酶（IKK）和NF-kappa B所必需的。RIP1在Lys-377位点的点突变（K377R）消除了它的多泛素化以及在RIP1缺陷细胞系中恢复IKK激活的能力。RIP1的K377R突变也阻止了TAK1和IKK复合物向TNF受体的募集。有趣的是，多泛素化的RIP1通过多泛素链和NEMO （IKK复合物的一个调节亚基）之间的结合来招募IKK。NEMO突变破坏其多泛素结合也会破坏IKK的激活。这些结果揭示了NEMO基本信号功能的生化机制，并提供了信号诱导的RIP1位点特异性泛素化是IKK激活所必需的直接证据。
The receptor interacting protein kinase 1 (RIP1) is essential for the activation of nuclear factor kappa B (NF-kappa B) by tumor necrosis factor alpha (TNF alpha). Here, we present evidence that TNF alpha induces the polyubiquitination of RIP1 at Lys-377 and that this polyubiquitination is required for the activation of I kappa B kinase (IKK) and NF-kappa B. A point mutation of RIP1 at Lys-377 (K377R) abolishes its polyubiquitination as well as its ability to restore IKK activation in a RIP1-deficient cell line. The K377R mutation of RIP1 also prevents the recruitment of TAK1 and IKK complexes to TNF receptor. Interestingly, polyubiquitinated RIP1 recruits IKK through the binding between the polyubiquitin chains and NEMO, a regulatory subunit of the IKK complex. Mutations of NEMO that disrupt its polyubiquitin binding also abolish IKK activation. These results reveal the biochemical mechanism underlying the essential signaling function of NEMO and provide direct evidence that signal-induced site-specific ubiquitination of RIP1 is required for IKK activation.