Mechanistic Elucidation of Inflammasome Assembly and Regulation

摘要 炎性小体是激活caspase子集的超分子信号复合体。 称为炎症性caspase，如caspase-1。在微生物的刺激下， 损伤相关信号，炎性小体聚集在一起，通过以下方式诱导宿主防御的第一道防线 细胞因子IL-1β和IL-18的蛋白水解性成熟，以及通过诱导嗜热性细胞死亡。 组装炎症体需要激活上游传感器、下游传感器 效应器，在大多数情况下是接头分子，如凋亡相关的斑点样蛋白 包含半胱氨酸天冬氨酸酶招募结构域(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 炎症性小体。尽管炎性小体在先天性免疫中具有重要的生物学意义，但没有 结构和机械信息是可用的。在本申请中，我们提出了结构化的、 AIM2、NLRP3和NAIP炎症体的生化、生物物理和细胞生物学研究 它们是ASC依赖性和ASC非依赖性炎性小体的代表性成员。 组装这些炎性小体的关键结构支架由以下组成 比林结构域的细丝(PYD)和半胱氨酸天冬氨酸氨基转移酶招募结构域(CARD)，并聚合 核苷酸结合区(NBD)的盘状结构。 炎症小体与许多人类疾病有关。最值得注意的是，未能 抑制炎性小体的活动与自体炎症有关，如家族性 地中海热和NLRP3相关周期性综合征，包括家族性感冒 自体炎症综合征、Muckle-Wells综合征和慢性婴儿神经系统 皮肤和关节综合征-新生儿发病的多系统炎症性疾病。AS 易感因素，炎症体成分蛋白与许多 炎症性疾病，如牛皮癣、狼疮，以及炎症性肠道疾病，如 溃疡性结肠炎和克罗恩病。

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.