Two Mechanistically and Temporally Distinct NF-κB Activation Pathways in IL-1 Signaling
Two Mechanistically and Temporally Distinct NF-κB Activation Pathways in IL-1 Signaling
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DOI：
10.1126/scisignal.2000387
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发表时间：
2009-10-20
影响因子：
7.3
通讯作者：
Inoue, Jun-Ichiro
中科院分区：
文献类型：
--
作者：
Yamazaki, Kohsuke;Gohda, Jin;Inoue, Jun-Ichiro
细胞因子白细胞介素-1（IL-1）通过激活转录因子核因子κ B（NF-κ B）介导免疫和炎症反应。尽管转化生长因子β激活激酶1（TAK 1）和丝裂原激活蛋白激酶（MAPK）激酶激酶3（MEKK 3）对于NF-κ B的IL-1依赖性激活都是至关重要的，但它们潜在的功能和物理相互作用仍不清楚。在这里，我们表明NAK 1介导的NF-κ B激活需要短暂形成信号复合物，其中包括肿瘤坏死因子受体相关因子6（TRAF 6）、MEKK 3和NAK 1。该复合物的形成需要TAK 1在赖氨酸209处的位点特异性赖氨酸63连接的多泛素化，可能由TRAF 6和Ubc 13催化。在TAK 1介导的NF-κ B活化后，TRAF 6随后通过MEKK 3独立于TAK 1活化NF-κ B，从而建立NF-κ B的连续活化，这是产生足够的细胞因子所需的。因此，我们提出，通过两种在TRAF 6处发生分歧的机制和时间上不同的MEKK 3依赖性途径协同激活NF-κ B，对免疫和炎症系统做出了关键贡献。
The cytokine interleukin-1 (IL-1) mediates immune and inflammatory responses by activating the transcription factor nuclear factor kappa B (NF-kappa B). Although transforming growth factor-beta-activated kinase 1 (TAK1) and mitogen-activated protein kinase (MAPK) kinase kinase 3 (MEKK3) are both crucial for IL-1-dependent activation of NF-kappa B, their potential functional and physical interactions remain unclear. Here, we showed that TAK1-mediated activation of NF-kappa B required the transient formation of a signaling complex that included tumor necrosis factor receptor-associated factor 6 (TRAF6), MEKK3, and TAK1. Site-specific, lysine 63-linked polyubiquitination of TAK1 at lysine 209, likely catalyzed by TRAF6 and Ubc13, was required for the formation of this complex. After TAK1-mediated activation of NF-kappa B, TRAF6 subsequently activated NF-kappa B through MEKK3 independently of TAK1, thereby establishing continuous activation of NF-kappa B, which was required for the production of sufficient cytokines. Therefore, we propose that the cooperative activation of NF-kappa B by two mechanistically and temporally distinct MEKK3-dependent pathways that diverge at TRAF6 critically contributes to immune and inflammatory systems.