CBAP functions as a novel component in chemokine-induced ZAP70-mediated T-cell adhesion and migration.
CBAP functions as a novel component in chemokine-induced ZAP70-mediated T-cell adhesion and migration.
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DOI：
10.1371/journal.pone.0061761
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Yen JJ
中科院分区：
文献类型：
--
作者：
Chiang YJ;Ho KC;Sun CT;Chiu JJ;Lee FJ;Liao F;Yang-Yen HF;Yen JJ
活化的趋化因子受体启动由内而外的信号传导以瞬时触发整合素的活化，这是一个涉及尚未完全表征的多个组分的过程。在这里，我们报告说，GM-CSF/IL-3/IL-5受体共同β链相关蛋白（CBAP）是优化这种由内而外的信号转导和激活整合素所必需的。首先，人Jurkat T细胞中CBAP表达的敲低导致体外CXC趋化因子配体12（CXCL 12）诱导的细胞迁移和整合素α4β1和αLβ2介导的细胞粘附减弱，这可以在鼠CBAP蛋白表达后得到充分拯救。新鲜分离的CBAP缺陷原代T细胞也表现出对CC趋化因子配体-21（CCL 21）和CXCL 12的趋化性减少，以及这些趋化因子诱导的体外T细胞粘附。分离的幼稚T细胞的连续转移证明CBAP缺陷显著降低体内淋巴结归巢能力。最后，由炎性趋化因子诱导的T细胞受体激活的T细胞的迁移也在CBAP缺陷细胞中减弱。进一步的分析表明，CBAP与整合素β1和ZAP 70组成性相关，并且CBAP是趋化因子诱导的talin-Vav 1复合物与整合素β1的初始结合以及促进随后ZAP 70介导的talin-Vav 1复合物解离和Vav 1磷酸化所必需的。在这样的整合素信号传导复合物中，CBAP可能作为接头发挥作用，并最终导致整合素α4β1和Rac 1的激活。总之，我们的数据表明，CBAP确实可以作为ZAP 70/Vav 1/talin复合物中的一种新型信号传导组分，并在调节趋化因子促进的T细胞运输中发挥重要作用。
Activated chemokine receptor initiates inside-out signaling to transiently trigger activation of integrins, a process involving multiple components that have not been fully characterized. Here we report that GM-CSF/IL-3/IL-5 receptor common beta-chain-associated protein (CBAP) is required to optimize this inside-out signaling and activation of integrins. First, knockdown of CBAP expression in human Jurkat T cells caused attenuated CXC chemokine ligand-12 (CXCL12)-induced cell migration and integrin α4β1- and αLβ2-mediated cell adhesion in vitro, which could be rescued sufficiently upon expression of murine CBAP proteins. Freshly isolated CBAP-deficient primary T cells also exhibited diminution of chemotaxis toward CC chemokine ligand-21 (CCL21) and CXCL12, and these chemokines-induced T-cell adhesions in vitro. Adoptive transfer of isolated naive T cells demonstrated that CBAP deficiency significantly reduced lymph node homing ability in vivo. Finally, migration of T cell-receptor–activated T cells induced by inflammatory chemokines was also attenuated in CBAP-deficient cells. Further analyses revealed that CBAP constitutively associated with both integrin β1 and ZAP70 and that CBAP is required for chemokine-induced initial binding of the talin-Vav1 complex to integrin β1 and to facilitate subsequent ZAP70-mediated dissociation of the talin-Vav1 complex and Vav1 phosphorylation. Within such an integrin signaling complex, CBAP likely functions as an adaptor and ultimately leads to activation of both integrin α4β1 and Rac1. Taken together, our data suggest that CBAP indeed can function as a novel signaling component within the ZAP70/Vav1/talin complex and plays an important role in regulating chemokine-promoted T-cell trafficking.
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影响因子：
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