Regulation of pathogen sensing and inflammation by NLR proteins

NLR 蛋白对病原体感应和炎症的调节

• 批准号: 9812277
• 负责人: Beckley K Davis
• 金额: $ 37.9万
• 依托单位: FRANKLIN AND MARSHALL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9812277
• 关键词: Affect; Affinity Chromatography; Attenuated; Autoimmune Diseases; Autoimmunity; Binding; Biochemical; Biological; Biological Response Modifiers; CASP1 gene; Cell Death; Cells; Chronic; Complex; Confocal Microscopy; Coupled; Cytosol; Data; Development; Disease; Endoplasmic Reticulum; Epithelial Cells; Equilibrium; FMNL1 gene; Family; Generations; Genetic Transcription; Goals; Health; Host Defense; Immune; Immune signaling; Immunity; Immunologics; In Situ; Infection; Inflammasome; Inflammation; Inflammatory; Insulin-Like Growth Factor I; Interferon Type I; Interferons; Interleukin-1 beta; Interleukin-18; Leucine; Leucine-Rich Repeat; Link; Location; Malignant Neoplasms; Mass Spectrum Analysis; Measures; Mediating; Metabolic Diseases; Metabolic syndrome; Microscopy; Molecular; N-terminal; NF-kappa B; Natural Immunity; Nuclear Envelope; Nucleic Acids; Nucleotides; Pathogen detection; Pathway interactions; Patients; Pattern; Pattern Recognition; Pattern recognition receptor; Post-Translational Protein Processing; Production; Protein Binding Domain; Proteins; Publishing; RNA Interference; Receptor Signaling; Regulation; Resolution; Role; Scaffolding Protein; Series; Signal Pathway; Signal Transduction; Signaling Molecule; Small Interfering RNA; T-Cell Receptor; TRAF6 gene; Techniques; Wegener' s Granulomatosis; Western Blotting; Yeasts; adaptive immunity; base; cell cortex; cytokine; design; experimental study; immunopathology; improved; insight; knock-down; macrophage; novel; pathogen; prevent; protein function; protein protein interaction; receptor; recruit; response; scaffold; screening; spatiotemporal; trafficking; tumorigenesis; yeast two hybrid system

Project Summary The NLR (nucleotide-binding domain, leucine-rich repeat containing protein, also known as NOD-like receptor) family is a diverse group of proteins that functions to regulate host immunity. Many of the NLRs have been shown to regulate inflammasome formation and control caspase-1 activation, IL-1β/IL-18 secretion and inflammatory cell death. In contrast a subset of NLR proteins negatively regulates different inflammatory pathways, typically via inhibitory interactions with key signaling molecules. Nonetheless the molecular mechanisms that control the negative regulation of inflammation are poorly understood. NLRC3 in particular has been shown to negatively regulate several key inflammatory pathways. For example, NLRC3 has been shown to inhibit NF-κB and PI3K pathways in response to TLR (or IGF-1R) signaling and proinflammatory cytokine secretion; alternatively, NLRC3 inhibits type I interferon production in response to cytosolic nucleic acid stimulation by regulating STING trafficking. The molecular mechanisms to allow for NLRC3 to function in diverse pathways are poorly understood. Understanding the molecular mechanisms of negative regulation of inflammation will be necessary for the generation of new strategies to improve health. Aim 1 of my proposal uses classic biochemical and cell biological techniques to examine the molecular determinants of novel protein-protein interactors with NLRC3. Our studies suggest that one of these interactors negatively regulates type I interferon production possibly by relocating NLRC3 to the cell cortex. I propose experiments to investigate how these interactions are mediated. In Aim 2 and 3 of my proposal, we will investigate the role of these protein-protein interactions using siRNA knockdown experiments and advanced microscopy to investigate the role of protein localization and trafficking in NLRC3- mediated inhibition of cellular pathways.

项目摘要 NLR(核苷酸结合域，富含亮氨酸重复序列的蛋白，也称为Nod样受体) 家族是一组不同的蛋白质，其功能是调节宿主免疫。许多NLR已经被展示出来 调节炎性小体形成，控制Caspase-1活化、IL-1β/IL-18分泌和炎症 细胞死亡。相比之下，NLR蛋白的一个子集负向调节不同的炎症途径，通常 通过抑制与关键信号分子的相互作用。尽管如此，控制这一现象的分子机制 对炎症的负面调控知之甚少。特别是NLRC3已经被证明是负面的 调节几个关键的炎症途径。例如，NLRC3已被证明抑制NF-κB和PI3K 反应TLR(或IGF-1R)信号和促炎细胞因子分泌的途径；或者，NLRC3 通过调节刺痛抑制胞浆核酸刺激时I型干扰素的产生 贩卖人口。NLRC3在不同途径中发挥作用的分子机制还知之甚少。 了解炎症负调控的分子机制对于 制定改善健康的新战略。我建议的目标1使用经典的生物化学和细胞生物学 用NLRC3研究新型蛋白质-蛋白质相互作用的分子决定因素的技术。我们的研究 提示这些相互作用之一可能通过重新定位来负性调节I型干扰素的产生。 NLRC3到细胞皮质。我提议用实验来研究这些相互作用是如何被调节的。在AIM 2 在我的提议中，我们将使用siRNA敲除来研究这些蛋白质-蛋白质相互作用的作用 实验和高级显微镜研究NLRC3-蛋白定位和运输的作用 介导对细胞通路的抑制。