COPs蛋白质负调节炎症小体活性的结构与功能研究

Inflammasomes is an important component of the innate immune system. When intracellular pattern recognition receptors (PPRs) encounter exogenous pathogen associated molecular patterns (PAMPs) or endogenous danger signal molecular patterns (DAMPs), they induce the formation of inflammasomes. As pro-caspase-1 activation platform, inflammasomes promote the mature and secretion of interleukin IL-1β and IL-18, whose potent proinflammatory activities direct host responses to infection and injury. Given the importance of inflammasomes play in inflammatory or reproductive disease, its crucial to contral the assembly and activity of inflammasomes. Canonical NLPR3 inflammasomes are supermolecualr complexes formed by receptor NLRP3, adaptor ASC and effector pro-caspase-1 mainly using PYD domain and CARD domains. Thus, PYD only proteins and CARD only proteins are potentially modifiers of inflammasomes. The three identified CARD-only proteins (COPs), the Pseudo - ICE/COP (CARD16), the INCA (CARD17) and ICEBERG (CARD18), are relatively short proteins of approximately 100 amino acids that essentially comprise a CARD domain. They all function in inflammasomes regulation, but not totally the same. Here, we will study the melecular mechanisms of negtive regulation of caspase-1 activity by these three COPs and the similiarities and differences, to further reveal the mechanism of assemly, acitivity and regulation of inflamasomes.

当胞内模式识别受体识别外源PAMPs或内源DAMPs后，引发炎症小体的形成。炎症小体作为pro-caspase-1的活化平台，促进白介素IL-1β和IL-18的成熟与分泌，引发宿主对感染与损失的免疫应答。鉴于炎症小体在疾病的防御和发生过程中的重要作用，对炎症小体组装和活性的精细调控至关重要。炎症小体超分子复合物的形成主要由组分中所含有的PYD结构域和CARD结构域的高聚形式所介导。所以只含有PYD或CARD结构域的蛋白则为炎症小体的重要调节子。目前主要发现三种COPs蛋白：CARD16，CARD17和CARD18，它们基本只由CARD结构域组成，且相似性非常高。三种COP蛋白在体内都能起到负调节caspase-1活性作用，但在机理上并不完全一样。本课题拟研究三种COP蛋白通过caspase-1调节炎症小体活性的分子机制，阐明三种COP蛋白调节炎症小体活性机制上的异同及其分子基础。