Ong Seow Theng, Freeley Michael, Skubis-Zegadło Joanna, Fazil Mobashar Hussain Urf Turabe, Kelleher Dermot, Fresser Friedrich, Baier Gottfried, Verma Navin Kumar, Long Aideen
From the From the Department of Clinical Medicine, Institute of Molecular Medicine, Trinity College Dublin, Dublin 8, Ireland.
From the From the Department of Clinical Medicine, Institute of Molecular Medicine, Trinity College Dublin, Dublin 8, Ireland, Department of Applied Pharmacy and Bioengineering, Medical University of Warsaw, 02-091 Warsaw, Poland.
J Biol Chem. 2014 Jul 11;289(28):19420-34. doi: 10.1074/jbc.M113.545863. Epub 2014 May 28.
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 Cϵ (PKCϵ) 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 PKCϵ. Both Rab5a and PKCϵ dynamically interact at the centrosomal region of migrating cells, and PKCϵ-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 PKCϵ-Rab5a-Rac1 axis regulates cytoskeleton remodeling and T-cell migration, both of which are central for the adaptive immune response.
Rab GTP酶控制膜运输和受体介导的内吞作用。在此背景下，Rab5a在细胞内运输和信号转导过程的空间调控中发挥重要作用。在此，我们报道了Rab5a在调节T细胞运动性方面以前未被描述的作用。我们发现Rab5a在迁移的T细胞中与蛋白激酶Cε（PKCε）发生物理结合。通过整合素LFA-1或趋化因子受体CXCR4刺激T细胞后，Rab5a在N端苏氨酸-7位点被PKCε磷酸化。Rab5a和PKCε在迁移细胞的中心体区域动态相互作用，并且PKCε介导的苏氨酸-7磷酸化调节Rab5a向细胞前沿的运输。此外，我们证明Rab5a苏氨酸-7磷酸化对于Rac1激活、肌动蛋白重排和T细胞运动性在功能上是必需的。我们提出了一种新机制，即PKCε-Rab5a-Rac1轴调节细胞骨架重塑和T细胞迁移，这两者对于适应性免疫反应都至关重要。
