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G-protein Coupled Receptor Mediated Chemoattractant Sensing and Phagocytosis

G 蛋白偶联受体介导的趋化剂感应和吞噬作用

基本信息

批准号：
7732578
负责人：
Tian Jin
金额：
$ 49.61万
依托单位：
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

项目摘要

We shed light into the long-standing question that is how a GPCR chemosensing network regulates the polarized reorganization of the actin cytoskeleton required for protrusion of the cell's front and retraction of its back during chemotaxis (see figure). In recent years, the Elmo (Engulfment and Motility) protein family has been implicated in actin cytoskeleton reorganization during both phagocytosis and chemotaxis. However, the molecular mechanisms by which these proteins regulate the actin dynamics in response to GPCR signaling are poorly understood. We have identified six Elmo homologs in D. discoideum and reported that ElmoA functions to maintain cell polarization by preventing excessive actin polymerization around the cell periphery during phagocytosis and chemotaxis. Elmo proteins positively regulate actin polymerization during cell migration and phagocytosis through activation of the small G-protein Rac. We identified an Elmo-like protein, ElmoA, in Dictyostelium discoideum that unexpectedly functions as a negative regulator of actin polymerization. Cells lacking ElmoA display an elevated rate of phagocytosis, increased pseudopod formation and excessive F-actin localization within pseudopods. ElmoA associates with cortical actin and myosin II. TIRF microscopic observations of functional ElmoA-GFP reveal that a fraction of ElmoA localizes near the presumptive actin/myosin II cortex and the levels of ElmoA and myosin II negatively correlate with that of polymerizing F-actin. F-actin-regulated dynamic dispersions of ElmoA and myosin II are interdependent. Taken together, our data suggest that ElmoA modulates actin/myosin II at the cortex to prevent excessive F-actin polymerization around the cell periphery, thereby maintaining proper cell shape during phagocytosis and chemotaxis (Isik, Brzostowski and Jin 2008, Developmental Cell, in press)

我们揭示了一个长期存在的问题，即GPCR化学传感网络如何调节肌动蛋白细胞骨架的极化重组，这是在趋化过程中细胞前部突出和后部缩回所必需的（见图）。近年来，埃尔莫（吞噬和运动）蛋白家族已被牵连在肌动蛋白细胞骨架重组过程中的吞噬和趋化。然而，这些蛋白调节肌动蛋白动力学响应GPCR信号的分子机制知之甚少。我们在D. discoideum等报道，ElmoA通过在吞噬和趋化过程中阻止细胞周围的过度肌动蛋白聚合来维持细胞极化。埃尔莫蛋白通过激活小G蛋白Rac在细胞迁移和吞噬过程中积极调节肌动蛋白聚合。我们在盘基网柄菌中发现了一种Elmo样蛋白ElmoA，它意外地充当肌动蛋白聚合的负调节剂。缺乏ElmoA的细胞表现出吞噬作用的速率升高，伪足形成增加和伪足内过量的F-肌动蛋白定位。ElmoA与皮质肌动蛋白和肌球蛋白II相关。功能性ElmoA-GFP的TIRF显微镜观察表明，一部分ElmoA定位在推定的肌动蛋白/肌球蛋白II皮质附近，ElmoA和肌球蛋白II的水平与聚合的F-肌动蛋白的水平呈负相关。F-肌动蛋白调节的ElmoA和肌球蛋白II的动态分散是相互依赖的。综上所述，我们的数据表明，ElmoA调节皮层的肌动蛋白/肌球蛋白II，以防止细胞周围的过度F-肌动蛋白聚合，从而在吞噬和趋化过程中保持适当的细胞形状（Isik，Brzostowski和Jin 2008，Developmental Cell，in press）