Phagosomal targeting of CARD proteins

翻译后摘要：CARD蛋白的吞噬体靶向 吞噬作用是细胞如巨噬细胞和树突状细胞结合、内化和杀伤的过程 微生物已知几种不同类型的受体识别微生物（直接或通过 调理作用）并触发吞噬作用。这些受体驱动的细胞生物学机制 吞噬作用依赖于特定的受体。因此，Fc受体介导的吞噬作用招募了一种独特的 比Dectin-1（β-葡聚糖受体）或补体受体介导的一组细胞骨架成分 吞噬作用吞噬作用与炎性细胞因子和趋化因子的启动密切相关 生产，尽管这些过程耦合的机制仍在阐明中。Caspase 激活和募集结构域（CARD）是在蛋白质中发现的保守的蛋白质-蛋白质相互作用结构域。 多种细胞质蛋白质是微生物识别和炎症信号传导的关键，包括Nod（核 寡聚化结构域）蛋白、Bcl 10、Nalp 1和许多其它蛋白。我们观察到， 蛋白质被募集到吞噬体中。我们假设CARD向吞噬体的募集是一个关键 吞噬和炎症信号整合的机制。在这项研究中，我们将定义 CARD蛋白被募集到吞噬体的机制以及CARD蛋白是否 仅被招募到特定类型的吞噬体（Aim 1）。我们将确定蛋白质之间的相互作用 所需的CARD蛋白的吞噬体，以及这些相互作用是否是重要的炎症 信号（目标2）。我们将确定激活吞噬体上的CARD蛋白（Nod 2）是否会改变其功能。 炎症信号传导的后果，以及这种靶向激活是否影响抗原呈递 以及所促进的适应性免疫反应的类型。简要说明：白色血细胞吞噬并杀死感染性微生物。它们还引发炎症 这些反应对于抵御感染至关重要。我们正在定义分子信号是如何 控制吞噬和杀死微生物过程的途径与信号传导有关， 激活炎症所需的途径。对这些通路的临床操作可能有助于 抑制不必要的炎症，或刺激有效的免疫防御。

Abstract: Phagosomal targeting of CARD proteins Phagocytosis is the process by which cells such as macrophages and dendritic cells bind, internalize, and kill microbes. Several different types of receptors are known to recognize microbes (either directly or through opsonization) and to trigger phagocytosis. The cell biological mechanisms by which these receptors drive phagocytosis are dependent the specific receptor. Thus, Fc-receptor mediated phagocytosis recruits a distinct set of cytoskeletal components than Dectin-1 (beta-glucan receptor) or complement receptor-mediated phagocytosis. Phagocytosis is tightly coupled to the initiation of inflammatory cytokine and chemokine production, although the mechanisms by which these processes are coupled are still being elucidated. Caspase Activation and Recruitment Domains (CARDs) are conserved protein-protein interaction domains found in a variety of cytoplasmic proteins key to microbial recognition and inflammatory signaling including Nod (nuclear oligomerization domain) proteins, Bcl10, Nalp1 and many others. We have observed that several CARD proteins are recruited to phagosomes. We hypothesize that CARD recruitment to phagosomes is a key mechanism by which signals for phagocytosis and inflammation are integrated. In this study, we will define the mechanism(s) by which CARD proteins are recruited to phagosomes and whether CARD proteins are recruited only to specific types of phagosomes (Aim1). We will determine what protein-protein interactions are required to get CARD proteins to phagosomes and whether these interactions are important for inflammatory signaling (Aim 2). We will determine whether activating a CARD protein (Nod2) on phagosomes alters its inflammatory signaling consequences, and whether such targeted activation influences antigen presentation and the type of adaptive immune response that is promoted. LAY SUMMARY: White blood cells eat and kill infectious microbes. They also initiate inflammatory responses that are crucial for defense against infection. We are defining how the molecular signaling pathways that control the processes of eating and killing microbes are connected to the signaling pathways required to activate inflammation. Clinical manipulation of these pathways may help suppress unwanted inflammation, or stimulate effective immune defenses.