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)

我们阐明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，使细胞的前部突出并在化学期间其背部缩回（见图）。近年来，Elmo（吞噬和运动性）蛋白家族在吞噬作用和趋化性过程中都与肌动蛋白细胞骨架重组有关。但是，这些蛋白质对GPCR信号的响应调节肌动蛋白动力学的分子机制知之甚少。我们已经确定了D. discoideum中的六个Elmo同源物，并报告了Elmoa通过在吞噬和趋化性期间预防细胞周围周围过度肌动蛋白聚合来维持细胞极化的功能。 ELMO蛋白通过小型G蛋白RAC的激活在细胞迁移和吞噬作用过程中积极调节肌动蛋白聚合。我们在迪斯特尔distelium discoideum中鉴定出一种Elmo样蛋白Elmoa，该蛋白质意外地作为肌动蛋白聚合的负调节剂。缺乏ELMOA的细胞显示出吞噬作用的升高，伪足的形成增加以及假脚架中的F-肌动蛋白定位过多。 Elmoa与皮质肌动蛋白和肌球蛋白II相关。功能性ELMOA-GFP的TIRF显微镜观察结果表明，在假定肌动蛋白/肌动蛋白II皮层附近的ELMOA的一部分定位于Elmoa和Elmoa和肌球蛋白II的水平，与聚合F-肌动蛋白的水平负相关。 ELMOA和肌球蛋白II的F-肌动调节的动态分散是相互依存的。综上所述，我们的数据表明，ELMOA在皮质处调节肌动蛋白/肌球蛋白II，以防止细胞周围周围的F-肌动蛋白聚合过度聚合，从而在吞噬和趋化性期间保持适当的细胞形状（Isik，Brzostowski和Jin 2008，Press）