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

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.

先天免疫是一种绝对重要的宿主防御机制，如果受到干扰，它本身就会在先天免疫防御机制中，引起大量的人类疾病。炎症小体是细胞质超分子复合物，可招募并激活炎症 caspase，特别是 caspase-1，介导促炎细胞因子的蛋白水解成熟 IL-1 家族中的一种，并诱导细胞死亡的快速炎症形式，称为细胞焦亡。细胞因子释放和细胞焦亡都向免疫系统的其余部分发出危险信号焦亡会杀死受感染或受损的细胞，以遏制疾病的传播。 NLRP3是引起该领域关注并正在兴起的炎症小体传感器是病原体和细胞诱导的膜损伤和细胞应激的通用传感器内源性危险信号，如细菌毒素尼日利亚菌素、细胞外ATP、尿酸晶体、胆固醇晶体、透明质酸和淀粉样蛋白-β原纤维。尿酸晶体诱导的炎症小体。激活是痛风严重关节炎症的原因，而其他刺激可能会导致 NLRP3 具有 N-三方结构。称为 PYD 的末端效应结构域，是一个中央核苷酸结合 ATP 酶结构域（NBD，也称为 PYD）被称为 NAHT）和 C 端 LRR 结构域激活后，NLRP3 会招募接头。 ASC 通过 PYD-PYD 相互作用，ASC 通过 CARD-CARD 进一步招募 caspase-1 相互作用诱导接近促进的 caspase 二聚化和激活。尽管 NLRP3 引起了学术和临床的极大兴趣，但其分子途径和 NLRP3 激活的机制仍不清楚，可能是由于其复杂的构象在本申请中，刚刚开始阐明转变和细胞内运输。我们建议通过以下方式阐明NLRP3炎症小体激活的功能机制研究构象转变和细胞内运输。