Gα13 and Rho Mediate Endosomal Trafficking of CXCR4 into Rab11+ Vesicles upon Stromal Cell-Derived Factor-1 Stimulation
Gα13 and Rho Mediate Endosomal Trafficking of CXCR4 into Rab11+ Vesicles upon Stromal Cell-Derived Factor-1 Stimulation
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DOI：
10.4049/jimmunol.1002019
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发表时间：
2011-01-15
影响因子：
4.4
通讯作者：
Hedin, Karen E.
中科院分区：
文献类型：
--
作者：
Kumar, Ashok;Kremer, Kimberly N.;Hedin, Karen E.
CXCR4 与其他 G 蛋白偶联受体一样，通过异三聚鸟嘌呤核苷酸结合蛋白（G 蛋白）发出信号来调节基因转录、迁移、发育、生长和转化。我们描述了 G 蛋白的一个以前未表征的功能：在受体运输中的作用。我们之前表明，在人 T 细胞中受到基质细胞衍生因子 1 或 CXCL12 (SDF-1) 刺激时，CXCR4 和 TCR 物理结合并形成异二聚体，以延长 ERK 激活，从而导致基因上调和细胞因子分泌。 CXCR4-TCR 异二聚体出现在细胞表面和细胞内区室中，响应 SDF-1。 CXCR4-TCR 异二聚体定位的细胞内区室和定位机制均尚未阐明。在本文中，我们描述了 CXCR4 内吞后运输所需的分子机制。在 SDF-1 刺激下，CXCR4 定位于 Rab11(+) 囊泡，这是微管组织中心和高尔基体附近的一个回收室。这种运输需要 CXCR4 C 末端尾部结构域，但不需要 CXCR4 泛素化位点。 TCR 也持续定位于 Rab11(+) 区室。将 CXCR4 运输到包含 TCR 的 Rab11(+) 内体中需要肌动蛋白聚合。此外，抑制Rho激活或消耗G alpha 13可以阻止CXCR4转运到Rab11(+)内体中，而不妨碍CXCR4内吞的能力。这些结果表明，在 SDF-1 处理后，G α 13 和 Rho 介导将 CXCR4 运输到 Rab11(+) 中所需的肌动蛋白聚合，回收内体区室，该区室也包含组成型回收 TCR，因此包含 CXCR4-TCR 异二聚体。据我们所知，这是 G α 13 作为受体贩运调节剂的首次报道。免疫学杂志，2011，186：951-958。
CXCR4, like other G protein-coupled receptors, signals via heterotrimeric guanine nucleotide-binding proteins (G proteins) to regulate gene transcription, migration, development, growth, and transformation. We describe a formerly uncharacterized function of a G protein: a role in receptor trafficking. We previously showed that CXCR4 and the TCR physically associate and form a heterodimer upon stromal cell-derived factor-1 or CXCL12 (SDF-1) stimulation in human T cells to prolong ERK activation and, thereby, lead to gene upregulation and cytokine secretion. The CXCR4-TCR heterodimers occur on the cell surface and in an intracellular compartment in response to SDF-1. Neither the intracellular compartment to which the CXCR4-TCR heterodimers localize nor the mechanism for localization has been elucidated. In this article, we characterize molecular mechanisms required for postendocytic trafficking of CXCR4. Upon SDF-1 stimulation, CXCR4 localizes to Rab11(+) vesicles, a recycling compartment near the microtubule organizing center and Golgi apparatus. This trafficking requires the CXCR4 C-terminal tail domain but not the CXCR4 ubiquitination sites. The TCR also constitutively localizes to this Rab11(+) compartment. Trafficking of CXCR4 into the Rab11(+), TCR-containing endosomes requires actin polymerization. Furthermore, inhibiting Rho activation or depleting G alpha 13 prevented trafficking of CXCR4 into the Rab11(+) endosomes without hindering the ability of CXCR4 to endocytose. These results indicated that, upon SDF-1 treatment, G alpha 13 and Rho mediate the actin polymerization necessary for trafficking CXCR4 into the Rab11(+), recycling endosomal compartment, which also contains constitutively recycling TCR and, thus, CXCR4-TCR heterodimers. To our knowledge, this is the first report of G alpha 13 as a mediator of receptor trafficking. The Journal of Immunology, 2011, 186: 951-958.