PDK1 nucleates T cell receptor-induced signaling complex for NF-κB activation
PDK1 nucleates T cell receptor-induced signaling complex for NF-κB activation
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DOI：
10.1126/science.1107107
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发表时间：
2005-04-01
期刊：
影响因子：
56.9
通讯作者：
Ghosh, S
中科院分区：
文献类型：
--
作者：
Lee, KY;D'Acquisto, F;Ghosh, S
在T细胞受体（TCR）接合后转录因子NF-κ B的活化对于适应性免疫应答期间的T细胞增殖和活化是重要的。最近的报道已经阐明了涉及蛋白激酶C θ（PKC θ）、支架蛋白CARD 11（也称为CARMA-1）、含有半胱天冬酶募集结构域（CARD）的蛋白Bcl 10和paracaspase（与半胱天冬酶相关的蛋白酶）MALT 1作为连接TCR与I κ B激酶（IKK）复合物的关键中间体的信号通路。然而，启动该信号传导途径活化的TCR近端事件仍然不清楚。我们证明，3-磷酸肌醇依赖性激酶1（PDK 1）通过调节PKC θ的激活和通过PKC θ和CARD 11的信号依赖性招募到脂筏在这一途径中具有重要作用。PDK 1相关PKC θ募集IKK复合物，而PDK 1相关CARD 11募集Bcl 10-MALT 1复合物，从而通过称为NEMO（NF-κ B必需修饰物）的IKK复合物亚基的Bcl 10-MALT 1依赖性泛素化激活IKK复合物。因此，PDK 1通过使T细胞中TCR诱导的NF-κ B活化途径成核而发挥关键作用。
Activation of the transcription factor NF-kappa B after engagement of the T cell receptor (TCR) is important for T cell proliferation and activation during the adaptive immune response. Recent reports have elucidated a signaling pathway that involves the protein kinase C theta (PKC theta), the scaffold protein CARD11 (also called CARMA-1), the caspase recruitment domain (CARD)-containing protein Bcl10, and the paracaspase (protease related to caspases) MALT1 as critical intermediates linking the TCR to the I kappa B kinase (IKK) complex. However, the events proximal to the TCR that initiate the activation of this signaling pathway remain poorly defined. We demonstrate that 3-phosphoinositide-dependent kinase 1 (PDK1) has an essential role in this pathway by regulating the activation of PKC theta and through signal-dependent recruiting of both PKC theta and CARD11 to lipid rafts. PDK1-associated PKC theta recruits the IKK complex, whereas PDK1-associated CARD11 recruits the Bcl10-MALT1 complex, thereby allowing activation of the IKK complex through Bcl10-MALT1-dependent ubiquitination of the IKK complex subunit known as NEMO (NF-kappa B essential modifier). Hence, PDK1 plays a critical role by nucleating the TCR-induced NF-kappa B activation pathway in T cells.