The role of DOCK2 and its regulatory mechanism in the innate immune system

中性粒细胞是高度活跃的白细胞，在对入侵病原体的先天免疫反应中发挥重要作用。中性粒细胞趋化性需要Rac激活，但在趋化剂受体下游发挥作用的Rac激活剂仍有待确定。在本研究中，我们分析了DOCK2在中性粒细胞趋化反应中的作用。虽然缺乏dock2的中性粒细胞向趋化剂源移动，但它们表现出异常的迁移行为，易位速度明显降低。在缺乏dock2的中性粒细胞中，趋化剂诱导的Rac1和Rac2的激活严重受损，导致前沿F-actin和磷脂酰肌醇3,4,5 -三磷酸（PIP3）的极化积累丧失。另一方面，我们发现DOCK2与PIP3结合，并以磷脂酰肌醇3-激酶（PI3K）依赖的方式易位到趋化中性粒细胞的前沿。这些结果表明，在中性粒细胞趋化过程中，DOCK2通过pip3依赖的膜易位和Rac激活来调节前缘的形成。除此之外，我们还发现DOCK2是一种Rac激活剂，对浆细胞样树突状细胞的迁移至关重要。因此，我们的研究结果表明，DOCK2不仅在获得性免疫系统中发挥重要作用，而且在先天免疫系统中也发挥重要作用。

Neutrophils are highly motile leukocytes and play important roles in the innate immune response to invading pathogens. Neutrophil chemotaxis requires Rac activation, yet the Rac activators functioning downstream of chemoattractant receptors remain to be determined. In this study, we have analyzed the role of DOCK2 in chemotactic response of neutrophils. Although DOCK2-deficient neutrophils moved toward the chemoattractant source, they exhibited abnormal migratory behavior with a marked reduction in translocation speed. In DOCK2-deficient neutrophils, chemoattractant-induced activation of both Rac1 and Rac2 were severely impaired, resulting in the loss of polarized accumulation of F-actin and phosphatidylinositol 3, 4, 5 -triphosphate (PIP3) at the leading edge. On the other hand, we found that DOCK2 associates with PIP3 and translocates to the leading edge of chemotaxing neutrophils in a phosphatidylinositol 3-kinase (PI3K) -dependent manner. These results indicate that during neutrophil chemotaxis DOCK2 regulates leading edge formation through PIP3-dependent membrane translocation and Rac activation. In addition to this, we revealed that DOCK2 is a Rac activator critical for migration of plasmacytoid dendritic cells. Our results thus indicate that DOCK2 plays an important role not only in the acquired, but also in the innate immune system.