G-protein Coupled Receptor Mediated Chemoattractant Sensing and Phagocytosis

我们阐明了一个长期存在的问题，即在趋化过程中，GPCR化学感应网络如何调节肌动蛋白细胞骨架的极化重组，而肌动蛋白细胞骨架的极化重组是细胞前部突起和后部收缩所必需的（见图）。近年来，吞噬和运动蛋白家族在吞噬和趋化过程中与肌动蛋白细胞骨架重组有关。然而，这些蛋白在响应GPCR信号时调节肌动蛋白动力学的分子机制尚不清楚。我们已经鉴定了6个Elmo同源物，并报道了ElmoA在吞噬和趋化过程中通过防止细胞周围过度的肌动蛋白聚合来维持细胞极化。

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)