Mechanistic Elucidation of Inflammasome Assembly and Regulation

炎症小体组装和调节的机制阐明

• 批准号: 9979736
• 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
• 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/9979736
• 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' s disease; Cryoelectron Microscopy; 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; 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 Onset Multisystem Inflammatory Disease; Neurologic; Nucleotides; Paper; Pathway interactions; Periodicity; Physiological; Play; Polymers; Predisposing Factor; Proteins; Psoriasis; Publishing; Regulation; Role; Science; Signal Transduction; Site; Structure; Syndrome; Ulcerative Colitis; Visualization; autoinflammatory; base; cytokine; familial cold autoinflammatory syndrome; human disease; infancy; marenostrin; member; microbial; mutant; nanometer; pathogen; polymerization; protein complex; receptor; reconstitution; recruit; scaffold; sensor; stoichiometry; therapy design/development

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.

摘要 炎性小体是一种超分子信号复合物，可激活半胱天冬酶的一个亚类 称为炎性半胱天冬酶如半胱天冬酶-1。在微生物的刺激下， 损伤相关的信号，炎性小体组装引发宿主防御的第一道防线， 通过细胞因子IL-1β和IL-18的蛋白水解成熟，以及通过诱导热凋亡细胞死亡。 炎性小体的组装需要激活上游传感器、下游传感器和下游传感器。 效应物，且在大多数情况下是衔接分子，如凋亡相关斑点样蛋白 含有胱天蛋白酶募集结构域（ASC）。根据是否需要ASC， 炎性小体可分为ASC依赖型和ASC非依赖型 炎性小体尽管炎性小体在先天免疫中的生物学重要性， 结构和机械信息是可用的。在本申请中，我们提出了结构， AIM 2、NLRP 3和NAIP炎性体的生物化学、生物物理学和细胞生物学研究， 其是ASC依赖性和ASC非依赖性炎性体的代表性成员。 这些炎性小体组装的关键结构支架由以下组成： Pyrin结构域（PYD）和半胱天冬酶募集结构域（CARD）的细丝，并聚合 通过核苷酸结合结构域（NBD）形成盘状结构。 炎性小体与许多人类疾病有关。最明显的是， 抑制炎性小体的活性与自身炎性疾病有关， 地中海热和NLRP 3相关的周期性综合征，包括家族性感冒 自身炎症综合征、Muckle-Wells综合征和慢性婴儿神经系统疾病 皮肤和关节综合征-新生儿发病的多系统炎性疾病。作为 诱发因素，炎性体组分蛋白已与许多 炎性疾病如牛皮癣、狼疮和炎性肠病如 溃疡性结肠炎和克罗恩病。