Mechanistic Elucidation of Inflammasome Assembly and Regulation

炎症小体组装和调节的机制阐明

基本信息

批准号：
9306767
负责人：
Hao Wu
金额：
$ 44.25万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9306767
关键词：
Adaptor Signaling Protein Apoptosis Apoptotic Attenuated Autoimmune Diseases Bacterial Proteins Binding Biochemical Biological Biophysics CASP1 gene CASP8 gene Caspase Cell Death Cells Cessation of life Chronic Complex Crohn&apos s disease Crystallography Cutaneous Data Death Domain Dimerization Disease Failure Familial Mediterranean Fever Familial amyloid nephropathy with urticaria and deafness Family Family member Fever Filament Foundations Gout Health Host Defense Human Imagery Immune response Immune signaling In Situ In Vitro Inflammasome Inflammation Inflammatory Inflammatory Bowel Diseases Interleukin-1 beta Interleukin-18 Interruption Length Leucine-Rich Repeat Ligands Link Lupus Molecular Molecular Machines Mutation N-terminal Natural Immunity Neonatal Neurologic Nucleotides Paper Pathway interactions Periodicity Physiological Play Polymers Predisposing Factor Proteins Psoriasis Publishing Recruitment Activity Regulation Role Science Signal Transduction Site Structure Syndrome Ulcerative Colitis autoinflammatory base cytokine dimer human disease infancy marenostrin member microbial mutant nanometer pathogen polymerization protein complex receptor reconstitution scaffold sensor stoichiometry therapy design/development

项目摘要

Abstract Inflammasomes are supramolecular signaling complexes that activate a subset of caspases known as inflammatory caspases such as caspase-1. Upon stimulation by microbial and damage-associated signals, inflammasomes assemble to elicit the first line of host defense by proteolytic maturation of cytokines IL-1β and IL-18, and by induction of pyroptotic cell death. Assembly of an inflammasome requires activation of an upstream sensor, a downstream effector, and in most cases an adaptor molecule such as apoptosis-associate speck-like protein containing a caspase recruitment domain (ASC). Depending on whether ASC is required, inflammasomes can be categorized into ASC-dependent and ASC-independent inflammasomes. Despite the biological importance of inflammasomes in innate immunity, no structural and mechanistic information is available. In this application, we propose structural, biochemical, biophysical and cell biological studies on AIM2, NLRP3 and NAIP inflammasomes, which are representative members of ASC-dependent and ASC-independent inflammasomes. The key structural scaffolds for the assembly of these inflammasomes are composed of filaments of Pyrin domains (PYD) and caspase recruitment domains (CARD), and polymerized disk-like structures by nucleotide-binding domains (NBD). Inflammasomes have been implicated in many human diseases. Most notably, failure to curb the activity of inflammasomes is linked to autoinflammatory conditions such as familial Mediterranean fever and NLRP3-associated periodic syndromes including familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and chronic infantile neurological cutaneous and articular syndrome–neonatal onset multisystem inflammatory disease. As predisposing factors, inflammasome component proteins have been associated with many inflammatory diseases such as psoriasis, lupus, and inflammatory bowel diseases such as ulcerative colitis and Crohn's diseases.

抽象的炎症是超分子信号传导复合物，激活了胱天蛋白酶的子集称为炎症性胱天蛋白酶，例如caspase-1。通过微生物刺激和与损害相关的信号，炎症组合组装，以引起第一线宿主防御细胞因子IL-1β和IL-18的蛋白水解成熟，并通过诱导凋亡细胞死亡。炎性体的组装需要激活上游传感器，下游效应子，在大多数情况下，衔接子分子（例如凋亡 - 促成蛋白）包含caspase募集域（ASC）。取决于是否需要ASC 炎症体可以归类为ASC依赖性和ASC独立炎症。尽管炎症体在先天免疫中具有生物学重要性，但没有可以提供结构和机械信息。在此应用中，我们提出了结构性的关于AIM2，NLRP3和NAIP炎症体的生化，生物物理和细胞生物学研究，是ASC依赖性和与ASC无关的炎症体的代表成员。这些炎症组件组装的关键结构支架由吡啶结构域（PYD）和caspase募集域（卡）的细丝，并聚合核苷酸结合结构域（NBD）的磁盘样结构。在许多人类疾病中都暗示了炎症。最值得注意的是，未能遏制炎症的活性与自发炎症条件（例如家族）有关地中海热和NLRP3相关的周期性综合征，包括家族性寒冷自发炎症综合征，陷入困境综合征和慢性基础设施神经系统皮肤和关节综合征 - 神经性发作多系统炎症性疾病。作为诱发因素，炎性组成分蛋白与许多牛皮癣，狼疮和炎症性肠道疾病等炎症性疾病，例如溃疡性结肠炎和克罗恩病。