Phagosomal targeting of CARD proteins

描述（由申请人提供）：CARD蛋白的吞噬体靶向吞噬作用是细胞（如巨噬细胞和树突细胞）结合、内化和杀死微生物的过程。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。这些受体驱动吞噬作用的细胞生物学机制依赖于特异性受体。因此，Fc受体介导的吞噬作用募集了一组不同于Dectin-1（β-葡聚糖受体）或补体受体介导的吞噬作用的细胞骨架组分。吞噬作用与炎性细胞因子和趋化因子产生的启动紧密相关，尽管这些过程的耦合机制仍在阐明中。半胱天冬酶激活和募集结构域（CARD）是在多种细胞质蛋白中发现的保守的蛋白质-蛋白质相互作用结构域，所述细胞质蛋白对微生物识别和炎症信号传导至关重要，包括Nod（核寡聚化结构域）蛋白、Bcl 10、Nalp 1和许多其他蛋白。我们已经观察到几种CARD蛋白被募集到吞噬体。我们假设CARD向吞噬体的募集是整合吞噬和炎症信号的关键机制。在这项研究中，我们将定义CARD蛋白被招募到吞噬体的机制，以及CARD蛋白是否只被招募到特定类型的吞噬体（Aim 1）。我们将确定什么样的蛋白质-蛋白质相互作用是使CARD蛋白进入吞噬体所必需的，以及这些相互作用对炎症信号传导是否重要（目的2）。我们将确定激活吞噬体上的CARD蛋白（Nod2）是否会改变其炎症信号传导的结果，以及这种靶向激活是否会影响抗原呈递和促进的适应性免疫反应的类型。 公共卫生相关性白色血细胞吞噬并杀死传染性微生物。它们还启动炎症反应，这对防御感染至关重要。我们正在定义控制进食和杀死微生物过程的分子信号通路如何与激活炎症所需的信号通路相连接。这些途径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。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE 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.