Role of CrkII in Fcγ receptor-mediated phagocytosis
Role of CrkII in Fcγ receptor-mediated phagocytosis
复制标题
DOI：
10.1074/jbc.m700823200
复制
发表时间：
2007-04-13
影响因子：
4.8
通讯作者：
Grinstein, Sergio
中科院分区：
文献类型：
--
作者：
Lee, Warren L.;Cosio, Gabriela;Grinstein, Sergio
Fc γ受体对IgG调理的病原体的吞噬作用需要肌动蛋白细胞骨架的广泛重塑，这是一个由小G T β Rac调节的过程。Vav被认为是负责激活Rac的鸟嘌呤核苷酸交换因子，但最近的证据表明，Fc γ受体介导的吞噬作用在缺乏所有三种Vav亚型的巨噬细胞中不受影响。因此，我们测试了另一种GEF DOCK 180是否参与Fc γ受体启动的吞噬作用。DOCK 180与衔接蛋白Crk相关，其介导GEF募集至酪氨酸磷酸化位点。发现CrkII和DOCK 180在吞噬杯中积聚。敲低Crk或DOCK 180在小鼠巨噬细胞使用小干扰RNA抑制吞噬IgG调理颗粒。此外，转染显性阴性CrkII阻止了DOCK 180的募集和吞噬杯处Rac的激活。这是Crk或DOCK 180在Fc γ受体介导的吞噬作用中的作用的首次报道。Crk-DOCK 180复合物参与凋亡细胞的清除，这与IgG调理颗粒的摄入不同，是一种抗炎过程。CrkII-DOCK 180也至少部分负责Fc γ受体的作用，这一发现意味着额外的平行途径必须解释相关的促炎作用。
Phagocytosis of IgG-opsonized pathogens by Fc gamma receptors requires extensive remodeling of the actin cytoskeleton, a process regulated by the small GTPase Rac. Vav was thought to be the guanine nucleotide exchange factor responsible for the activation of Rac, but recent evidence indicates that Fc gamma receptor-mediated phagocytosis is unaffected in macrophages lacking all three isoforms of Vav. We therefore tested whether another GEF, DOCK180, participates in Fc gamma receptor-initiated phagocytosis. DOCK180 associates with the adaptor protein Crk, which mediates recruitment of the GEF to sites of tyrosine phosphorylation. CrkII and DOCK180 were found to accumulate at the phagocytic cup. Knockdown of Crk or DOCK180 in murine macrophages using small interfering RNA inhibited phagocytosis of IgG-opsonized particles. Moreover, transfection of dominant negative CrkII prevented both recruitment of DOCK180 and the activation of Rac at the phagocytic cup. This is the first report of a role for either Crk or DOCK180 in Fc gamma receptor-mediated phagocytosis. The Crk-DOCK180 complex is involved in the clearance of apoptotic cells, which unlike the ingestion of IgG-opsonized particles, is an anti-inflammatory process. The finding that CrkII-DOCK180 is also responsible, at least in part, for the effects of Fc gamma receptors implies that additional, parallel pathways must account for the associated pro-inflammatory effect.