Signal transduction from endosomes/lysosomes to the cytoskeleton during phagocytosis

许多细胞从环境中吸收粒子。在吞噬体内，颗粒逐渐成熟，与不同分子组成的细胞器融合。酶降解内化的大分子，以便为细胞代谢提供燃料。分散的观察表明，运输路线和吞噬体的成熟速度比以前预期的要异质得多。格里菲斯新概念吞噬体个体预测信号从吞噬体进入细胞质，这可以调节细胞生理学的许多方面。我们已经注意到，突变体缺乏降解内化细菌所需的机器组件，或过度表达另一种，通过增加食物摄取率来补偿。因为这是从吞噬体到颗粒摄取所需的机器的信号传导的两个例子，我们已经对这些突变细胞系进行了基因表达谱分析，并确定了被错误调节的共同候选基因，因此可能参与信号传导过程。我们建议研究这些基因的影响，如果人为的过度表达或负性遗传干扰。如果这种突变体的吞噬特性发生改变，我们将发现基因产物在细胞中的位置，以及它是否影响同一筛选中鉴定的其他基因的表达。通过这些手段，我们应该能够重建至少一部分迄今为止模糊的信号级联从内体的细胞骨架的机器，介导在质膜的内化。

Many cells take up particles from their environment. Within phagosomes, particles mature gradually fusing with organelles of different molecular compositions. Enzymes degrade the internalized macromolecules in order to provide fuel for the cellular metabolism. Scattered observations indicate that trafficking routes and maturation velocities of phagosomes are much more heterogeneous than previously anticipated. Griffiths¿ new concept of ¿phagosome individuality¿ predicts signalling from phagosomes into the cytoplasm, which could regulate many aspects of cell physiology. We have noted that mutants lacking a component of the machinery required to degrade internalized bacteria, or overexpressing another, compensate by increasing the rate of food uptake. Because these are two examples of signalling from the phagosome to the machinery needed for particle uptake, we have performed gene-expression profiling of these mutant cell lines, and identified common candidate genes that are misregulated and therefore may be involved in the signalling process. We propose to study the effect of these genes if misregulated artificially by overexpression or negative genetic interference. If such a mutant is altered in its phagocytic properties, we will find out where in the cell the gene product localizes and whether it influences the expression of other genes identified in the same screen. By these means we should be able to reconstruct at least part of the hitherto obscure signalling cascade from endosomes to the cytoskeletal machinery that mediates internalization at the plasma membrane.