Functional and Structural Dissection of Inflammasome Activation

项目总结/摘要 炎性小体是多蛋白质复合物，其响应于感染或其他炎症反应而在胞质溶胶中组装。 有害刺激炎性小体作为平台激活炎性半胱天冬酶蛋白酶， 半胱天冬酶-1活性胱天蛋白酶-1通过将pro-IL 1B和pro-IL 18细胞因子切割成它们的 活性和分泌形式。活性胱天蛋白酶-1还可以通过以下方式触发细胞死亡的裂解形式，称为细胞凋亡， 切割并激活一种叫做Gasdermin D的成孔蛋白。炎性小体在 启动宿主对多种病毒、细菌、真菌和原生动物病原体的防御。此外，遗传 来自人类和小鼠的证据已经证实，不适当的炎性小体激活可以导致 严重的自身免疫和炎症驱动的疾病。然而，分子机制如何 炎性小体检测病原体并被激活仍然知之甚少。该提案重点 对NLRP 1炎性小体，这似乎有一个新的，但知之甚少的机制， activation.先前的研究表明，小鼠NLRP 1被芽孢杆菌产生的毒素激活， 炭疽，但这是如何发生的，以及是否有病原体编码的人类NLRP 1激活剂 仍不清楚为了弥补我们知识中的这些空白，本提案有两个目标：1.确定 NLRP 1激活的生化机制; 2.识别激活的新型病原体相关酶 NLRP 1.这些目标的完成将增加我们对先天性免疫系统的机制的理解。 免疫系统检测并响应病原体。

Project Summary/Abstract Inflammasomes are multi-protein complexes that assemble in the cytosol in response to infection or other noxious stimuli. Inflammasomes serve as platforms to activate inflammatory caspase proteases such as Caspase-1. Active Caspase-1 initiates inflammation by cleaving pro-IL1B and pro-IL18 cytokines into their active and secreted forms. Active Caspase-1 can also trigger a lytic form of cell death, called pyroptosis, by cleaving and activating a pore-forming protein called Gasdermin D. Inflammasomes play critical roles in initiating host defense against diverse viral, bacterial, fungal and protozoan pathogens. In addition, genetic evidence from humans and mice has established that inappropriate inflammasome activation can cause severe autoimmune and inflammation-driven diseases. However, the molecular mechanisms of how inflammasomes detect pathogens and become activated remain poorly understood. This proposal focuses on the NLRP1 inflammasome, which appears to have a novel but poorly understood mechanism of activation. Prior studies have demonstrated that mouse NLRP1 is activated by a toxin produced by Bacillus anthracis, but how this occurs and whether there are pathogen-encoded activators of human NLRP1 remains unclear. To address these gaps in our knowledge, this proposal has two aims: 1. Determine the biochemical mechanism of NLRP1 activation; 2. Identify novel pathogen-associated enzymes that activate NLRP1. Completion of these aims will increase our understanding of the mechanisms by which the innate immune system detects and responds to pathogens.