Phosphorylation of Rab5a Protein by Protein Kinase Cε Is Crucial for T-cell Migration
Phosphorylation of Rab5a Protein by Protein Kinase Cε Is Crucial for T-cell Migration
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DOI：
10.1074/jbc.m113.545863
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发表时间：
2014-07-11
影响因子：
4.8
通讯作者：
Long, Aideen
中科院分区：
文献类型：
--
作者：
Ong, Seow Theng;Freeley, Michael;Long, Aideen
Rab GTP酶控制膜运输和受体介导的内吞作用。在这一背景下，Rab5a在细胞内运输和信号转导过程的空间调控中发挥着重要作用。在这里，我们报告了以前未知的Rab5a在调节T细胞运动中的作用。我们发现Rab5a在迁移的T细胞中与蛋白激酶C epsilon(PKC Epsilon)有物理上的联系。通过整合素LFA-1或趋化因子受体CXCR4刺激T细胞后，Rab5a在N端的Thr-7位点被PKC epsilon磷酸化。Rab5a和PKC epsilon在迁移细胞的中心体区域动态相互作用，PKC epsilon介导的Thr-7磷酸化调节Rab5a向细胞前沿的转运。此外，我们还证明了Rab5a Thr-7的磷酸化是rac1激活、肌动蛋白重排和T细胞运动所必需的。我们提出了一种新的机制，通过PKC epsilon-Rab5a-rac1轴调节细胞骨架重塑和T细胞迁移，这两者都是获得性免疫反应的中心。
Rab GTPases control membrane traffic and receptor-mediated endocytosis. Within this context, Rab5a plays an important role in the spatial regulation of intracellular transport and signal transduction processes. Here, we report a previously uncharacterized role for Rab5a in the regulation of T-cell motility. We show that Rab5a physically associates with protein kinase C epsilon (PKC epsilon) in migrating T-cells. After stimulation of T-cells through the integrin LFA-1 or the chemokine receptor CXCR4, Rab5a is phosphorylated on an N-terminal Thr-7 site by PKC epsilon. Both Rab5a and PKC epsilon dynamically interact at the centrosomal region of migrating cells, and PKC epsilon-mediated phosphorylation on Thr-7 regulates Rab5a trafficking to the cell leading edge. Furthermore, we demonstrate that Rab5a Thr-7 phosphorylation is functionally necessary for Rac1 activation, actin rearrangement, and T-cell motility. We present a novel mechanism by which a PKC epsilon-Rab5a-Rac1 axis regulates cytoskeleton remodeling and T-cell migration, both of which are central for the adaptive immune response.