Phagosomal targeting of CARD proteins

CARD 蛋白的吞噬体靶向

• 批准号: 8074174
• 负责人: David M. Underhill
• 金额: $ 4.83万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-15 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8074174
• 关键词: Actinin; Actins; Adjuvant; Affect; Agonist; Antigen Presentation; Antigen Presentation Pathway; Antigens; Autophagocytosis; Binding; Biological; Caspase; Cells; Clinical; Complement Receptor; Coupled; Crohn' s disease; Cytoplasmic Protein; Cytoskeleton; Dendritic Cells; Disease susceptibility; Eating; Fc Receptor; Gene Proteins; Genes; Genome; Immune; Immune response; Immunologic Receptors; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Intracellular Membranes; Lead; Leukocytes; Link; Macrophage Activation; Mediating; Membrane; Microbe; Molecular; Movement; Mucosal Immunity; Mutation; Nuclear; Organelles; Pathway interactions; Phagocytosis; Phagolysosome; Phagosomes; Process; Production; Property; Protein Binding Domain; Proteins; Recruitment Activity; Role; Route; Signal Pathway; Signal Transduction; Signaling Molecule; Susceptibility Gene; Tertiary Protein Structure; abstracting; beta-glucan receptor; chemokine; cytokine; dectin 1; in vivo; killings; macrophage; mannose receptor; microbial; novel; particle; protein protein interaction; receptor

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.

摘要：吞噬体靶向CARD蛋白 吞噬作用是巨噬细胞和树突状细胞等细胞结合、内化和杀伤的过程。 微生物。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)，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个独特的 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。吞噬作用与炎症细胞因子和趋化因子的启动密切相关 生产，尽管这些过程的耦合机制仍在阐明中。半胱氨酸酶 激活和募集结构域(CARD)是一种保守的蛋白质相互作用结构域，存在于 多种与微生物识别和炎症信号转导有关的细胞质蛋白，包括NOD(核 寡聚域)蛋白、Bcl10、Nalp1等。我们观察到有几张卡片 蛋白质被招募到吞噬小体中。我们假设吞噬小体的卡片招募是一个关键 吞噬和炎症信号整合的机制。在这项研究中，我们将定义 CARD蛋白被招募到吞噬小体的机制(S)以及CARD蛋白是否被 仅招募到特定类型的吞噬小体(Aim1)。我们将确定什么是蛋白质-蛋白质相互作用 需要获得吞噬小体的CARD蛋白，以及这些相互作用是否对炎症重要 信令(目标2)。我们将确定激活吞噬小体上的卡片蛋白(NOD2)是否会改变其 炎症信号后果，以及这种靶向激活是否影响抗原提呈 以及被促进的适应性免疫反应的类型。文章摘要：白血球吞噬并杀死感染微生物。它们还会引发炎症 对防御感染至关重要的反应。我们正在定义分子信号如何 控制摄食和杀死微生物过程的通路与信号转导有关 激活炎症所需的途径。对这些通路的临床操作可能会有所帮助 抑制不必要的炎症，或刺激有效的免疫防御。