The LIM protein Ajuba influences interleukin-1-induced NF-κB activation by affecting the assembly and activity of the protein kinase Cζ/p62/TRAF6 signaling complex
The LIM protein Ajuba influences interleukin-1-induced NF-κB activation by affecting the assembly and activity of the protein kinase Cζ/p62/TRAF6 signaling complex
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DOI：
10.1128/mcb.25.10.4010-4022.2005
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发表时间：
2005-05-01
影响因子：
5.3
通讯作者：
Longmore, GD
中科院分区：
文献类型：
--
作者：
Feng, YF;Longmore, GD
Zyxin/Ajuba 家族的胞质 LIM 结构域蛋白具有从细胞粘附位点穿梭到细胞核的潜力，因此可以成为环境信号的候选传感器。为了了解 Ajuba 在信号转导途径中的作用，我们使用 Ajuba 的 LIM 结构域区域进行了酵母双杂交筛选。我们确定非典型蛋白激酶 C (aPKC) 支架蛋白 p62 作为 Ajuba 结合伴侣。 p62 的一个突出功能是通过形成 aPKC/p62/TRAF6 多蛋白信号复合物来响应白介素-I (IL-1) 和肿瘤坏死因子信号传导来调节 NF-kappa B 激活。除了 p62 之外，我们发现 Ajuba 还与肿瘤坏死因子受体相关因子 6 (TRAF6) 和 PKC zeta 相互作用。 Ajuba 将 TRAX6 招募到 p62 并在体外激活 PKC zeta 活性，并且是 PKC zeta 的底物。 Ajuba 无效小鼠胚胎成纤维细胞 (MEF) 和肺在 IL-1 刺激后 NF-κ B 激活存在缺陷，并且肺 IKK 活性受到抑制。原代 MEF 中 Ajuba 的过表达可增强 IL-1 刺激后的 NF-κ B 活性。我们认为 Ajuba 是 IL-1 信号通路的新胞质成分，通过影响 aPKC/p62/TRAF6 多蛋白信号复合物的组装和活性来调节 IL-1 诱导的 NF-kappa B 激活。
The Zyxin/Ajuba family of cytosolic LIM domain-containing proteins has the potential to shuttle from sites of cell adhesion into the nucleus and thus can be candidate transducers of environmental signals. To understand Ajuba's role in signal transduction pathways, we performed a yeast two-hybrid screen with the LIM domain region of Ajuba. We identified the atypical protein kinase C (aPKC) scaffold protein p62 as an Ajuba binding partner. A prominent function of p62 is the regulation of NF-kappa B activation in response to interleukin-I (IL-1) and tumor necrosis factor signaling through the formation of an aPKC/p62/TRAF6 multiprotein signaling complex. In addition to p62, we found that Ajuba also interacted with tumor necrosis factor receptor-associated factor 6 (TRAF6) and PKC zeta. Ajuba recruits TRAX6 to p62 and in vitro activates PKC zeta activity and is a substrate of PKC zeta. Ajuba null mouse embryonic fibroblasts (MEFs) and lungs were defective in NF-kappa B activation following IL-1 stimulation, and in lung IKK activity was inhibited. Overexpression of Ajuba in primary MEFs enhances NF-kappa B activity following IL-1 stimulation. We propose that Ajuba is a new cytosolic component of the IL-1 signaling pathway modulating IL-1-induced NF-kappa B activation by influencing the assembly and activity of the aPKC/p62/TRAF6 multiprotein signaling complex.