The 3BP2 Adapter Protein Is Required for Chemoattractant-Mediated Neutrophil Activation
The 3BP2 Adapter Protein Is Required for Chemoattractant-Mediated Neutrophil Activation
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DOI：
10.4049/jimmunol.1103184
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发表时间：
2012-09-01
影响因子：
4.4
通讯作者：
Rottapel, Robert
中科院分区：
文献类型：
--
作者：
Chen, Grace;Dimitriou, Ioannis;Rottapel, Robert
3BP 2是一种含有pleckstrin同源性和Src同源性2结构域的衔接蛋白，在巨像症（一种罕见的常染色体显性人类骨骼疾病）中突变。以前，我们已经证明了3BP 2在外周B细胞发育和腹膜B1和脾边缘区B细胞介导的抗体反应中的功能作用。在这项研究中，我们表明，3BP 2所需的G蛋白偶联受体介导的中性粒细胞功能。来自3BP 2缺陷型（Sh 3bp 2（-/-））小鼠的中性粒细胞未能响应趋化肽fMLF的梯度而使其肌动蛋白细胞骨架发生改变或迁移。Sh 3bp 2（-/-）中性粒细胞未能响应fMLF灌注粘附、爬行和移出血管系统。3BP 2是Src家族激酶、小GT受体Rac 2、嗜中性粒细胞超氧阴离子产生的最佳活化以及单核细胞增生李斯特菌体内细菌清除所必需的。在Sh 3bp 2（-/-）中性粒细胞中观察到的功能缺陷可能部分解释为未能完全激活Vav 1鸟嘌呤核苷酸交换因子和正确定位P-Rex 1鸟嘌呤核苷酸交换因子在迁移细胞的前沿。我们的研究结果揭示了G蛋白偶联受体介导的中性粒细胞功能中衔接蛋白3BP 2的必要性。免疫学杂志，2012，189：2138-2150。
3BP2 is a pleckstrin homology and Src homology 2 domain-containing adapter protein mutated in cherubism, a rare autosomal-dominant human bone disorder. Previously, we have demonstrated a functional role for 3BP2 in peripheral B cell development and in peritoneal B1 and splenic marginal zone B cell-mediated Ab responses. In this study, we show that 3BP2 is required for G protein-coupled receptor-mediated neutrophil functions. Neutrophils derived from 3BP2-deficient (Sh3bp2(-/-)) mice failed to polarize their actin cytoskeleton or migrate in response to a gradient of chemotactic peptide, fMLF. Sh3bp2(-/-) neutrophils failed to adhere, crawl, and emigrate out of the vasculature in response to fMLF superfusion. 3BP2 is required for optimal activation of Src family kinases, small GTPase Rac2, neutrophil superoxide anion production, and for Listeria monocytogenes bacterial clearance in vivo. The functional defects observed in Sh3bp2(-/-) neutrophils may partially be explained by the failure to fully activate Vav1 guanine nucleotide exchange factor and properly localize P-Rex1 guanine nucleotide exchange factor at the leading edge of migrating cells. Our results reveal an obligate requirement for the adapter protein 3BP2 in G protein-coupled receptor-mediated neutrophil function. The Journal of Immunology, 2012, 189: 2138-2150.