Elucidating the functional mechanism of NLRP3 inflammasome activation

先天免疫是一种绝对必要的宿主防御机制，如果受到干扰，它本身就可以 会导致大量的人类疾病。在先天免疫防御机制中， 炎性小体是胞浆中的超分子复合体，它招募和激活炎症 半胱氨酸天冬氨酸酶，特别是半胱氨酸氨基转移酶-1，介导促炎症细胞因子的蛋白分解成熟 在IL-1家族中，并诱导一种称为下垂的快速炎症形式的细胞死亡。 细胞因子的释放和上睑下垂都预示着免疫系统的其余部分和 上睑下垂会杀死受感染或受损的细胞，以遏制疾病的传播。 NLRP3是目前备受业界关注的炎症体传感器 作为膜损伤和细胞应激的通用传感器，由病原体和 细菌毒素黑素、胞外ATP、尿酸结晶等内源性危险信号， 胆固醇晶体、透明质酸和淀粉样蛋白-β纤维。尿酸结晶致炎小体 激活是痛风患者严重关节炎症的原因，而其他刺激可能有助于 心血管和神经退行性疾病。NLRP3有一个三方组织，N- 末端效应结构域，称为PYD，中央核苷酸结合ATPase结构域(NBD，也 称为Nacht)和C-端LRR结构域。激活后，NLRP3招募适配器 ASC通过PYD-PYD互动和ASC通过Card-Card进一步招募caspase-1 相互作用诱导邻近促进的caspase二聚化和激活。 尽管NLRP3在学术和临床上引起了极大的兴趣，但其分子途径和 NLRP3的激活机制尚不清楚，可能是由于复杂的构象 转变和细胞内贩运才刚刚开始被阐明。在此应用程序中， 我们建议通过以下途径阐明NLRP3炎症体激活的作用机制 研究构象转变和细胞内运输。

Innate immunity is an absolutely essential host defense mechanism that, if perturbed, can itself cause a large number of human diseases. Among innate immune defense mechanisms, inflammasomes are cytosolic supramolecular complexes that recruit and activate inflammatory caspases, in particular caspase-1, to mediate proteolytic maturation of proinflammatory cytokines in the IL-1 family, and induce the rapid inflammatory form of cell death known as pyroptosis. Cytokine release and pyroptosis both signal danger to the rest of the immune system and pyroptosis kills infected or damaged cells to curtail the spread of the disease. NLRP3 is the inflammasome sensor that has caught the attention of the field and is emerging to be a general sensor of membrane damage and cellular stress, induced by pathogens and endogenous danger signals such as bacterial toxin nigericin, extracellular ATP, uric acid crystals, cholesterol crystals, hyaluronan and amyloid-β fibrils. Uric acid crystal-induced inflammasome activation is causal to severe joint inflammation in gout, and other stimuli could contribute to cardiovascular and neurodegenerative diseases. NLRP3 has a tripartite organization with an N- terminal effector domain known as PYD, a central nucleotide-binding ATPase domain (NBD, also known as NACHT) and a C-terminal LRR domain. Upon activation, NLRP3 recruits the adaptor ASC through PYD-PYD interactions and ASC further recruits caspase-1 through CARD-CARD interactions to induce proximity-promoted caspase dimerization and activation. Despite the great academic and clinical interest on NLRP3, the molecular pathway and mechanism for NLRP3 activation remain unclear, likely due to the complicated conformational transitions and intracellular trafficking that are just beginning to be elucidated. In this application, we propose to elucidate the functional mechanism of NLRP3 inflammasome activation by investigating the conformational transitions and intracellular trafficking.