Molecular mechanism of NLRP3 inflammasome activation

项目摘要 含NACHT、LRR和PYD结构域的蛋白3（NLRP 3）是一种重要的蛋白质， 形成NLRP 3炎性体（一种细胞内分子平台）的先天免疫系统 其驱动半胱天冬酶-1活化和生物活性IL-1β和IL-18的分泌。此外 其在先天免疫中的保护作用，NLRP 3炎性体的异常激活 有助于几种遗传性和获得性炎症性疾病的发病机制， 如Cryopyrin相关的自身炎症综合征，痛风，克罗恩病，阿尔茨海默氏症 疾病、糖尿病和动脉粥样硬化。尽管进行了广泛的研究， 导致NLRP 3炎性体活化的机制仍然是难以捉摸的。最近，蛋白激酶Nek 7 已发现其独立于激酶活性介导NLRP 3炎性体活化。 然而，目前尚不清楚Nek 7如何与NLRP 3炎性小体激活机制相关。 我们最近的研究暗示Nek 7磷酸化在NLRP 3炎性小体中起关键作用 activation.在本申请中，我们的目的是阐明Nek 7介导的 NLRP 3炎性体激活，并确定一种新的调节剂在这一途径中的作用。我们 这些结果有望为NLRP 3炎性小体激活提供新的机制见解 并可能指导治疗NLRP 3驱动的新治疗策略的开发。 炎症性疾病。

Project Summary NACHT, LRR and PYD domains-containing protein 3 (NLRP3) is a critical component of the innate immune system that forms the NLRP3 inflammasome, an intracellular molecular platform that drives caspase-1 activation and the secretion of biologically active IL-1β and IL-18. In addition to its protective role in innate immunity, aberrant activation of the NLRP3 inflammasome contributes to the pathogenesis of several inherited and acquired inflammatory disorders, such as Cryopyrin-associated autoinflammatory syndrome, gout, Crohn's disease, Alzheimer's disease, diabetes and atherosclerosis. Despite extensive investigation, the molecular mechanism leading to NLRP3 inflammasome activation remains elusive. Recently, the protein kinase Nek7 has been found to mediate NLRP3 inflammasome activation independently of its kinase activity. However, it is unknown how Nek7 is mechanistically linked to NLRP3 inflammasome activation. Our recent studies implicate a critical role for Nek7 phosphorylation in NLRP3 inflammasome activation. In this application we aim to elucidate the molecular mechanism of Nek7-mediated NLRP3 inflammasome activation and determine the role of a novel regulator in this pathway. Our results are expected to provide new mechanistic insights into NLRP3 inflammasome activation and might guide the development of novel therapeutic strategies for treating NLRP3-driven inflammatory diseases.