CARD-only protein regulation of cytosolic Pattern Recognition Receptor signaling

细胞质模式识别受体信号传导的仅 CARD 蛋白调节

• 批准号: 10415886
• 负责人: Andrea Dorfleutner
• 金额: $ 57.88万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10415886
• 关键词: Acute; Address; Affect; Attenuated; Biochemical; Biological; Bone Marrow; CASP1 gene; Caspase; Cell Death; Cells; Communicable Diseases; Competitive Binding; Complement; Complex; Data; Development; Disease; Disease model; Failure; Goals; Health; Homeostasis; Host Defense; Human; Immune response; Immune signaling; Infection; Inflammasome; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Interferon Type I; Knowledge; Link; Mediating; Molecular; Molecular Disease; Molecular Genetics; Mouse Protein; Mus; NF-kappa B; Natural Immunity; Pathology; Pathway interactions; Patients; Pattern Recognition; Pattern recognition receptor; Peptides; Physiological; Production; Protein Binding Domain; Protein Family; Proteins; Receptor Signaling; Regulation; Research; Resolution; Rodent; Role; Signal Pathway; Signal Transduction; Therapeutic; Time; Transgenic Mice; base; cytokine; design; genetic approach; genetic regulatory protein; human disease; improved; in vivo; inhibitor; innate immune pathways; insight; macrophage; mouse model; mutant; novel; novel therapeutics; overexpression; prevent; programs; protein expression; protein function; receptor; recruit; response; tissue injury; tool; treatment strategy

Although, acute inflammatory responses have a protective role in innate immunity and host defense, dysregulation and failure to properly resolve these responses cause inflammatory and infectious disease. Several key cytosolic pattern recognition receptors signal through proteins containing the Caspase recruitment domain (CARD), which is a protein-protein interaction domain, leading to inflammasome and NF-kB activation, and inflammatory cytokine and type I interferon (IFN) production. However, the molecular mechanisms by which these pathways are controlled to limit excessive and detrimental inflammatory responses, are largely unknown. Three small proteins containing only a CARD, which are referred to as CARD-only proteins (COPs) exist in humans, but like the related PYRIN domain-only proteins (POPs), are lacking from mice, which supports the notion that these inflammatory responses require a tight control in particular in humans. COPs have been identified over a decade ago, but except of a few initial overexpression studies, nothing is known about the precise role of these proteins. We demonstrated key inflammasome regulatory activities of the three POPs encoded in humans using a comprehensive analysis in humans and transgenic mice, and we hypothesize that similarly, COPs will have an important role in regulating inflammatory responses and our preliminary data indicate that COPs have a broader role than POPs by targeting several key pattern recognition receptors. The research outlined in this proposal is geared to define the precise role of each COP in macrophages during infection and inflammation, using a comprehensive analysis combining biochemical, molecular and genetic approaches. We will also define their role during inflammatory and infectious disease, using novel generated transgenic mice for all three COPs. We expect that our research will uncover novel molecular control mechanisms that prevent inappropriate inflammation and will therefore be highly significant and relevant for better understanding innate immunity and inflammatory disease and for providing the basis for developing novel therapies to benefit patients and will therefore positively affect human health.

虽然，急性炎症反应在先天免疫和宿主防御中具有保护作用， 调控失调和未能妥善解决这些反应会导致炎症和传染病。 几种关键的胞质模式识别受体通过含有Caspase募集的蛋白发出信号 结构域(CARD)，这是一个蛋白质-蛋白质相互作用结构域，导致炎症体和核因子-kB激活， 炎性细胞因子和I型干扰素的产生。然而，分子机制是通过 这些途径被控制以限制过度和有害的炎症反应，主要是 未知。 三种只含有一张卡片的小蛋白，被称为仅卡片蛋白(COPS) 存在于人类中，但与相关的吡咯环结构域仅蛋白(POP)一样，在小鼠中缺乏，而小鼠则缺乏 支持这样的观点，即这些炎症反应需要严格控制，特别是在人类身上。警察 早在十多年前就被发现了，但除了少数最初的过度表达研究外，什么都不知道。 这些蛋白质的确切作用。我们展示了三种炎症性小体的关键调控活动。 我们在人类和转基因小鼠身上进行了全面的分析，在人类身上编码了POP，我们 假设同样，COPS将在调节炎症反应和我们的 初步数据表明，通过针对几个关键模式，警察比持久性有机污染物具有更广泛作用 识别受体。本提案中概述的研究旨在确定每个缔约方会议的确切作用 在巨噬细胞感染和炎症过程中，使用综合分析结合生化， 分子和遗传方法。我们还将确定它们在炎症性和传染性疾病中的作用， 使用新产生的转基因小鼠来治疗所有三种COP。 我们希望我们的研究将发现新的分子控制机制，以防止 不适当的炎症，因此对更好地理解先天具有重要意义和相关性 免疫和炎症性疾病，并为开发新的治疗方法提供基础 因此，它将对人类健康产生积极影响。

项目成果

NLRP3 licenses NLRP11 for inflammasome activation in human macrophages.

• DOI: 10.1038/s41590-022-01220-3
• 发表时间: 2022-06
• 期刊: NATURE IMMUNOLOGY
• 影响因子: 30.5
• 作者: Gangopadhyay, Anu;Devi, Savita;Tenguria, Shivendra;Carriere, Jessica;Huyen Nguyen;Jager, Elisabeth;Khatri, Hemisha;Chu, Lan H.;Ratsimandresy, Rojo A.;Dorfleutner, Andrea;Stehlik, Christian
• 通讯作者: Stehlik, Christian