Elucidating the functional mechanism of NLRP3 inflammasome activation

阐明NLRP3炎症小体激活的功能机制

基本信息

批准号：
10720435
负责人：
Hao Wu
金额：
$ 70.8万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-26 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10720435
关键词：
ATPase Domain Academia Aging Amyloid Amyloid beta-Protein Antibodies Architecture Attention Bacterial Toxins Binding Biochemical C-terminal CASP1 gene Cardiovascular Diseases Caspase Cell Death Cellular Membrane Cellular Stress Centrosome Chiroptera Cholesterol Clinical Clinical Trials Complex Cryo-electron tomography Cryoelectron Microscopy Data Defense Mechanisms Dependence Development Dimerization Disease Dynein ATPase Family Filament Fishes Genetic Genetic Screening Gout HDAC6 gene Host Defense Host Defense Mechanism Hyaluronan IL18 gene Image Immune Immune system Immunologic Surveillance Industry Infection Inflammasome Inflammation Inflammatory Interleukin-1 Interleukin-1 beta Length Leucine-Rich Repeat Ligands Lipopolysaccharides Liposomes Location Mediating Membrane Microtubule-Organizing Center Microtubules Molecular Molecular Conformation Multiprotein Complexes Mutagenesis Mutation N-terminal Natural Immunity Neurodegenerative Disorders Nigericin Nucleotides Particulate Pathway interactions Phosphotransferases Play Potassium Process Protein Engineering Proteins PubMed Publications Regulation Rest Role Signal Transduction Stimulus Structure Syndrome Toll-like receptors Uric Acid Vesicle Visualization autoinflammatory cell injury conformational conversion cytokine extracellular human disease insight interest joint inflammation malignant neurologic neoplasms marenostrin monomer nervous system disorder particle pathogen reconstitution recruit response scaffold sensor targeted treatment therapeutic target trafficking trans-Golgi Network

ATPase Domain Academia Aging Amyloid Amyloid beta-Protein Antibodies Architecture Attention Bacterial Toxins Binding Biochemical C-terminal CASP1 gene Cardiovascular Diseases Caspase Cell Death Cellular Membrane Cellular Stress Centrosome Chiroptera Cholesterol Clinical Clinical Trials Complex Cryo-electron tomography Cryoelectron Microscopy Data Defense Mechanisms Dependence Development Dimerization Disease Dynein ATPase Family Filament Fishes Genetic Genetic Screening Gout HDAC6 gene Host Defense Host Defense Mechanism Hyaluronan IL18 gene Image Immune Immune system Immunologic Surveillance Industry Infection Inflammasome Inflammation Inflammatory Interleukin-1 Interleukin-1 beta Length Leucine-Rich Repeat Ligands Lipopolysaccharides Liposomes Location Mediating Membrane Microtubule-Organizing Center Microtubules Molecular Molecular Conformation Multiprotein Complexes Mutagenesis Mutation N-terminal Natural Immunity Neurodegenerative Disorders Nigericin Nucleotides Particulate Pathway interactions Phosphotransferases Play Potassium Process Protein Engineering Proteins PubMed Publications Regulation Rest Role Signal Transduction Stimulus Structure Syndrome Toll-like receptors Uric Acid Vesicle Visualization autoinflammatory cell injury conformational conversion cytokine extracellular human disease insight interest joint inflammation malignant neurologic neoplasms marenostrin monomer nervous system disorder particle pathogen reconstitution recruit response scaffold sensor targeted treatment therapeutic target trafficking trans-Golgi Network

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项目摘要

Innate immunity is an absolutely essential host defense mechanism that, if perturbed, can itself cause a large number of human diseases. Among innate immune defense mechanisms, inflammasomes are cytosolic supramolecular complexes that recruit and activate inflammatory caspases, in particular caspase-1, to mediate proteolytic maturation of proinflammatory cytokines in the IL-1 family, and induce the rapid inflammatory form of cell death known as pyroptosis. Cytokine release and pyroptosis both signal danger to the rest of the immune system and pyroptosis kills infected or damaged cells to curtail the spread of the disease. NLRP3 is the inflammasome sensor that has caught the attention of the field and is emerging to be a general sensor of membrane damage and cellular stress, induced by pathogens and endogenous danger signals such as bacterial toxin nigericin, extracellular ATP, uric acid crystals, cholesterol crystals, hyaluronan and amyloid-β fibrils. Uric acid crystal-induced inflammasome activation is causal to severe joint inflammation in gout, and other stimuli could contribute to cardiovascular and neurodegenerative diseases. NLRP3 has a tripartite organization with an N- terminal effector domain known as PYD, a central nucleotide-binding ATPase domain (NBD, also known as NACHT) and a C-terminal LRR domain. Upon activation, NLRP3 recruits the adaptor ASC through PYD-PYD interactions and ASC further recruits caspase-1 through CARD-CARD interactions to induce proximity-promoted caspase dimerization and activation. Despite the great academic and clinical interest on NLRP3, the molecular pathway and mechanism for NLRP3 activation remain unclear, likely due to the complicated conformational transitions and intracellular trafficking that are just beginning to be elucidated. In this application, we propose to elucidate the functional mechanism of NLRP3 inflammasome activation by investigating the conformational transitions and intracellular trafficking.

先天免疫是绝对必要的宿主防御机制，如果受到干扰，可以引起大量人类疾病。在先天的免疫反义机制中，炎性症是胞质超分子复合物，可募集和激活炎症 caspase，特别是caspase-1，介导促炎细胞因子的蛋白水解成熟在IL-1家族中，并诱导被称为凋亡的细胞死亡的快速炎症形式。细胞因子释放和凋亡都对其他免疫系统的危险表示危险，并且凋亡杀死感染或受损的细胞，以减少疾病的传播。 NLRP3是引起了该领域的注意的炎性传感器成为膜损伤和细胞应激的一般传感器，由病原体和内源性危险信号，例如细菌毒素nigeryin，细胞外ATP，尿酸晶体，胆固醇晶体，透明质酸和淀粉样蛋白β纤维。尿酸晶体诱导的炎性体激活是痛风中严重关节感染的因果，其他刺激可能有助于心血管和神经退行性疾病。 NLRP3拥有一个三方组织末端效应域称为PYD，一种中央核苷酸ATPase结构域（NBD，也是称为NACHT）和C末端LRR结构域。激活后，NLRP3招募适配器通过PYD-PYD相互作用ASC，ASC通过卡卡进一步募集caspase-1 相互作用以诱导接近促进的caspase二聚体和激活。尽管对NLRP3具有很大的学术和临床兴趣，但分子途径和 NLRP3激活的机制尚不清楚，这可能是由于复杂的构象所致刚刚开始阐明的过渡和细胞内贩运。在此应用程序中我们建议通过调查会议过渡和细胞内贩运。