Role of chimaerins, a group of Rac-specific GTPase activating proteins, in T-cell receptor signaling
Role of chimaerins, a group of Rac-specific GTPase activating proteins, in T-cell receptor signaling
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DOI：
10.1016/j.cellsig.2007.12.015
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发表时间：
2008-04-01
影响因子：
4.8
通讯作者：
Bustelo, Xose R.
中科院分区：
文献类型：
--
作者：
Caloca, Maria Jose;Delgado, Pilar;Bustelo, Xose R.
Chimaerins是GTP酶激活蛋白，以二酰基甘油依赖性方式抑制GTP水解酶Rac 1。迄今为止，嵌合蛋白的研究主要在神经元细胞中进行。在这里，我们表明，α 2-和β 2-嵌合蛋白在T细胞中以不同的水平表达，并且它们参与T细胞受体信号传导。与此一致，我们已经观察到α 2-和β 2-嵌合蛋白易位到T细胞/B细胞免疫突触，并使用获得和丧失功能的方法，证明了它们的催化活性对于抑制T细胞受体和Vav 1依赖的转录因子NF-AT的刺激是重要的。基于诱变的方法已经揭示了在T细胞应答期间有助于嵌合蛋白生物程序的分子决定因素。出乎意料的是，我们已经发现，嵌合蛋白的易位T细胞/B细胞免疫突触不依赖于典型的结合二酰基甘油的C1区的这些GTP酶激活蛋白。综上所述，这些结果确定嵌合蛋白作为下调Rac 1在T淋巴细胞中的候选者，此外，揭示了一种新的调节机制，介导其在T细胞中的激活。(C)2007爱思唯尔公司All rights reserved.
Chimaerins are GTPase-activating proteins that inactivate the GTP-hydrolase Rac1 in a diacylglycerol-dependent manner. To date, the study of chimaerins has been done mostly in neuronal cells. Here, we show that alpha 2- and beta 2-chimaerin are expressed at different levels in T-cells and that they participate in T-cell receptor signaling. In agreement with this, we have observed that alpha 2- and beta 2-chimaerins translocate to the T-cell/B-cell immune synapse and, using both gain- and loss-of-function approaches, demonstrated that their catalytic activity is important for the inhibition of the T-cell receptor- and Vav1-dependent stimulation of the transcriptional factor NF-AT. Mutagenesis-based approaches have revealed the molecular determinants that contribute to the biological program of chimaerins during T-cell responses. Unexpectedly, we have found that the translocation of chimaerins to the T-cell/B-cell immune synapse does not rely on the canonical binding of diacylglycerol to the C1 region of these GTPase-activating proteins. Taken together, these results identify chimaerins as candidates for the downmodulation of Rac1 in T-lymphocytes and, in addition, uncover a novel regulatory mechanism that mediates their activation in T-cells. (C) 2007 Elsevier Inc. All rights reserved.