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首页> 外文期刊>Molecular and Cellular Biology >TRAF6 Is Required for TRAF2-Dependent CD40 Signal Transduction in Nonhemopoietic Cells
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TRAF6 Is Required for TRAF2-Dependent CD40 Signal Transduction in Nonhemopoietic Cells

机译：在非造血细胞中依赖TRAF2的CD40信号转导需要TRAF6

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The emerging role of CD40, a tumor necrosis factor (TNF) receptor family member, in immune regulation, disease pathogenesis, and cancer therapy necessitates the analysis of CD40 signal transduction in a wide range of tissue types. In this study we present evidence that the CD40-interacting proteins TRAF2 and TRAF6 play an important physiological role in CD40 signaling in nonhemopoietic cells. Using mutational analysis of the CD40 cytoplasmic tail, we demonstrate that the specific binding of TRAF2 to CD40 is required for efficient signaling on the NF-κB, Jun N-terminal protein kinase (JNK), and p38 axis. In fibroblasts lacking TRAF2 or in carcinoma cells in which TRAF2 has been depleted by RNA interference, the CD40-mediated activation of NF-κB and JNK is significantly reduced, and the activation of p38 and Akt is severely impaired. Interestingly, whereas the TRAF6-interacting membrane-proximal domain of CD40 has a minor role in signal transduction, studies utilizing TRAF6 knockout fibroblasts and RNA interference in epithelial cells reveal that the CD40-induced activation of NF-κB, JNK, p38, and Akt requires the integrity of TRAF6. Furthermore, we provide evidence that TRAF6 regulates CD40 signal transduction not only through its direct binding to CD40 but also indirectly via its association with TRAF2. These observations provide novel insight into the mechanisms of CD40 signaling and the multiple roles played by TRAF6 in signal transduction.
机译：CD40是肿瘤坏死因子（TNF）受体家族成员，在免疫调节，疾病发病机理和癌症治疗中起着新兴作用，因此有必要对多种组织类型的CD40信号转导进行分析。在这项研究中，我们提供证据表明，与CD40相互作用的蛋白TRAF2和TRAF6在非造血细胞的CD40信号传导中起着重要的生理作用。使用CD40细胞质尾部的突变分析，我们证明TRAF2与CD40的特异性结合是NF-κB，Jun N末端蛋白激酶（JNK）和p38轴上有效信号传递所必需的。在缺少TRAF2的成纤维细胞中或在TRAF2已被RNA干扰耗尽的癌细胞中，CD40介导的NF-κB和JNK活化显着降低，并且p38和Akt的活化受到严重损害。有趣的是，尽管CD40的TRAF6相互作用膜近端结构域在信号转导中起较小作用，但利用TRAF6敲除成纤维细胞和上皮细胞中RNA干扰的研究表明CD40诱导了NF-κB，JNK，p38和Akt的激活需要TRAF6的完整性。此外，我们提供的证据表明，TRAF6不仅通过直接与CD40结合，而且通过与TRAF2的结合间接调节CD40信号转导。这些发现为CD40信号传导机制以及TRAF6在信号转导中的多种作用提供了新颖的见解。

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