Phagosomal targeting of CARD proteins

描述(申请人提供)：吞噬体靶向吞噬卡片蛋白吞噬作用是指巨噬细胞和树突状细胞等细胞结合、内化和杀死微生物的过程。已知有几种不同类型的受体可以识别微生物(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定的受体。因此，Fc受体介导的吞噬作用与Dectin-1(β-葡聚糖受体)或补体受体介导的吞噬作用相比，招募了一组不同的细胞骨架成分。吞噬作用与炎症细胞因子和趋化因子的产生密切相关，尽管这些过程的耦合机制仍在阐明中。Caspase激活和募集结构域(CADS)是一类保守的蛋白质-蛋白质相互作用结构域，存在于多种细胞质蛋白中，对微生物识别和炎症信号转导起关键作用，包括NOD(核寡聚化结构域)蛋白、Bcl10、Nalp1等。我们观察到有几种CARD蛋白被募集到吞噬小体中。我们假设吞噬小体的卡片募集是吞噬和炎症信号整合的关键机制。在这项研究中，我们将确定CARD蛋白被招募到吞噬小体的机制(S)，以及CARD蛋白是否只被特定类型的吞噬小体招募(AIM1)。我们将确定将CARD蛋白送到吞噬小体所需要的蛋白质-蛋白质相互作用，以及这些相互作用是否对炎症信号重要(目标2)。我们将确定激活吞噬小体上的卡片蛋白(NOD2)是否改变其炎症信号后果，以及这种靶向激活是否影响抗原递呈和被促进的获得性免疫反应的类型。 与公共健康相关白血球吞噬并杀死感染微生物。它们还会引发炎症反应，这对防御感染至关重要。我们正在定义控制吞食和杀死微生物过程的分子信号通路是如何与激活炎症所需的信号通路相联系的。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.