Rac regulates PtdInsP3 signaling and the chemotactic compass through a redox-mediated feedback loop
Rac regulates PtdInsP3 signaling and the chemotactic compass through a redox-mediated feedback loop
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DOI：
10.1182/blood-2010-09-310383
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发表时间：
2011-12-01
期刊：
影响因子：
20.3
通讯作者：
Glogauer, Michael
中科院分区：
文献类型：
--
作者：
Kuiper, Jan W. P.;Sun, Chunxiang;Glogauer, Michael
定向细胞迁移是有效的中性粒细胞易位到感染部位的基本要求，并需要建立一个极化的细胞，其特征在于面向趋化梯度的肌动蛋白丰富的前沿。磷脂酰肌醇（3，4，5）-三磷酸[PtdIns（3，4，5）P-3]在上梯度前缘的不对称积累是极化的标志，并调节前缘质膜上各种效应蛋白的募集和定位。趋化因子的浅梯度如何触发并维持PtdIns（3，4，5）P-3的更陡的细胞内梯度是白细胞趋化性研究中的关键问题。我们的数据表明，中性粒细胞向化学引诱物N-甲酰-L-甲硫氨酰-L-亮氨酰-L-苯丙氨酸的迁移依赖于吞噬NADPH氧化酶（NOX 2）产生的活性氧，以及随后的氧化和磷酸酶和张力蛋白同系物的抑制。此外，我们发现，下游的PtdIns（3，4，5）P-3，包括磷酸化的AKT，Rac激活，去帽的肌动蛋白丝，定向迁移的事件，可以减弱活性氧清除剂或基因消融的NOX 2。使用Rac突变体，在他们的能力有缺陷的激活NOX 2，我们表明，Rac调节氧化还原介导的反馈回路，介导的中性粒细胞的定向迁移。（血。2011;118（23）：6164-6171）
Directional cell migration is an essential requirement for efficient neutrophil translocation to sites of infection and requires the establishment of a polarized cell characterized by an actin-rich leading edge facing the chemoattractant gradient. The asymmetrical accumulation of phosphatidylinositol(3,4,5)-trisphosphate [PtdIns(3,4,5)P-3] in the up-gradient leading edge is a hallmark of polarization and regulates the recruitment and localization of various effector proteins at the leading-edge plasma membrane. How shallow gradients of chemoattractants trigger and maintain a much steeper intracellular gradient of PtdIns(3,4,5)P-3 is a critical question in the study of leukocyte chemotaxis. Our data demonstrate that the migration of neutrophils toward the chemoattractant N-formyl-L-methionyl-L-leucyl-L-phenylalanine depends on the generation of reactive oxygen species by the phagocytic NADPH oxidase (NOX2) and subsequent oxidation and inhibition of phosphatase and tensin homolog. Moreover, we show that events downstream of PtdIns(3,4,5)P-3, including phosphorylation of AKT, Rac activation, uncapping of actin filaments, and directional migration, can be attenuated by ROS scavengers or genetic ablation of NOX2. Using Rac mutants that are defective in their ability to activate NOX2, we show that Rac regulates a redox-mediated feedback loop that mediates directional migration of neutrophils. (Blood. 2011;118(23):6164-6171)