G-protein Coupled Receptor Mediated Chemoattractant Sensing and Phagocytosis

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趋化过程中细胞前部突起和后部收缩所需的肌动蛋白细胞骨架的极化重组(见图)。近年来，吞噬和运动蛋白家族参与了吞噬和趋化过程中肌动蛋白的细胞骨架重组。然而，这些蛋白质调节肌动蛋白动态以响应GPCR信号的分子机制却知之甚少。我们已经在盘状芽孢杆菌中鉴定了六个Elmo同源物，并报道了ElmoA通过在吞噬和趋化过程中阻止细胞周围过度的肌动蛋白聚合来维持细胞极化。 Elmo蛋白通过激活小G蛋白Rac，正向调节细胞迁移和吞噬过程中的肌动蛋白聚合。我们在盘基网柄菌中发现了一种Elmo样蛋白ElmoA，它出人意料地作为肌动蛋白聚合的负调节因子发挥作用。缺乏ElmoA的细胞表现为吞噬速率增加，伪足形成增加，伪足内F-肌动蛋白定位过多。ElmoA与皮质肌动蛋白和肌球蛋白II联系在一起。对ElmoA-GFP功能的TIRF显微镜观察显示，ElmoA的一小部分位于推测的肌动蛋白/肌球蛋白II皮质附近，ElmoA和肌球蛋白II的水平与聚合F-肌动蛋白的水平呈负相关。F-肌动蛋白调控的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调节皮质上的肌动蛋白/肌球蛋白II，以防止F-肌动蛋白在细胞外围过度聚合，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，《发育细胞》，出版中)

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)