Host-derived extracellular vesicles in inflammatory caspase activation

炎性小体相关的半胱天冬酶如半胱天冬酶-1、半胱天冬酶-4和半胱天冬酶-11是炎性小体相关的半胱天冬酶的亚类。 胱天蛋白酶家族专门执行细胞死亡的裂解形式和基于IL-1的胱天蛋白酶 炎症反应。这些炎性半胱天冬酶的激活与 通过典型和非典型的感染和细胞扰动的先天免疫检测 炎性小体炎性小体是细胞质中的多蛋白复合物， 对多种病原体相关分子模式（PAMPs）的反应，包括核酸 酸、毒素、鞭毛蛋白和细胞壁成分以及内源性危险信号（危险- 相关的分子模式，或DAMP），如ATP和尿酸晶体。大会 炎性体复合物导致炎性半胱天冬酶的自身蛋白水解激活。 炎症性半胱天冬酶的酶活性形式激活称为 gasdermin D，其通过质膜穿孔裂解细胞。活性caspase-1也 将炎性细胞因子pro-IL-1β和pro-IL-18切割成其活性形式。炎性 半胱天冬酶对于启动针对多种炎症的炎症反应是重要的， 病原体包括细菌和病毒。炎性半胱天冬酶在脓毒症中也起着关键作用， 一种与感染有关的严重危及生命的疾病。细胞外囊泡（EV）是 我们的活细胞将大量的膜结合结构释放到细胞外空间。 EV与蛋白质、脂质和RNA包装在一起，并且EV已经成为一种重要的免疫模式。 所有三种货物的细胞间转移。电动汽车货物是功能性的，可以调节生理 的受体细胞。然而，EV在炎性体信号传导中的作用很差 明白该提案旨在通过三个方面全面解决这一关键的知识差距 具体目标。目的1将表征宿主来源的EV对炎性半胱天冬酶的影响 通过PAMP激活。目标2和3将通过以下方式证明分子和细胞机制： 其中宿主来源的EV调节炎性半胱天冬酶的PAMP活化。总之，这 该提案将揭示宿主来源的EV在炎症反应中的新作用， 宿主防御对人类传染病和败血症具有重要意义。

Inflammasome related caspases such as caspase-1, caspase-4, and caspase-11 are a subset of the caspase family specialized in executing a lytic form of cell death and IL-1 cytokine-based inflammatory response. The activation of these inflammatory caspases is strongly coupled to innate immune detection of infections and cellular perturbations via canonical and noncanonical inflammasomes. Inflammasomes are multiprotein complexes in the cytosol assembled in response to wide variety of pathogen-associated molecular patterns (PAMPs) including nucleic acids, toxins, flagellin, and cell wall components and endogenous danger signals (danger- associated molecular patterns, or DAMPs) such as ATP and uric acid crystals. The assembly of inflammasome complex leads to the autoproteolytic activation of inflammatory caspases. Enzymatically active versions of inflammatory caspases activate a pore forming protein called gasdermin D, which lyses the cells via plasma membrane perforation. Active caspase-1 also cleaves the inflammatory cytokines pro-IL-1β and pro-IL-18 into their active forms. Inflammatory caspases are important for initiating the inflammatory response against a wide variety of pathogens including bacteria and viruses. Inflammatory caspases also play crucial roles in sepsis, a major life-threatening condition associated with infections. Extracellular vesicles (EVs) are membrane-bound structures abundantly released by our living cells into the extracellular space. EVs are packaged with proteins, lipids, and RNAs, and EVs have emerged as a crucial mode of inter-cellular transfer of all three cargoes. EV-cargoes are functional and modulate the physiology of the recipient cells. However, the role of EVs in the inflammasome signaling is poorly understood. This proposal seeks to comprehensively address this critical knowledge gap in three specific aims. Aim 1 will characterize the impact of host-derived EVs on inflammatory caspase activation by PAMPs. Aims 2 and 3 will demonstrate the molecular and cellular mechanisms by which the host-derived EVs regulate PAMP-activation of inflammatory caspases. In summary, this proposal will reveal a new role for host-derived EVs in inflammasome responses in the context of host defense with great implications for human infectious diseases and sepsis.