Identification of the molecular regulation between cell survival and cell death in response to infection induced inflammasome activation.

决定炎症体激活是否导致细胞死亡或存活的分子机制 以及免疫细胞的激活，目前尚不清楚。炎症体是一种蛋白质复合体，其功能是 细胞病原体传感器。在感觉到病原体时，半胱氨酸蛋白酶家族的成员之一， Caspase-1在炎性小体中被激活。活性caspase-1裂解Gasdermin-D(GSDMD)，即 随后在质膜上形成孔，导致一种形式的细胞死亡，称为 上睑下垂。矛盾的是，质膜上GSDMD孔的形成并不总是导致 致上睑下垂。已经描述了运输所需的内体分选复合体(ESCRT) 导致膜修复。目前还不知道是什么上行信号决定了 受损的膜是否修复。这是一个重要的问题，因为如果不理解这一点， 炎症体激活的有益部分(细胞因子成熟)不能从 有害且高度炎症性下垂。根据我们的初步数据，我们的假设是 ESCRT复合体被caspase-2酶裂解失活，从而促进下睑下垂。这 我们的初步工作支持了这一假说，在这项工作中，细菌毛孔形成毒素触发了 病原体检测反应和刺激炎症小体。在这个系统中，caspase-2与 切割ESCRT相关蛋白Alix。这项研究的基本原理是，理解这一点 炎症小体驱动的下垂的新调节可能导致新的和创新的方法来治疗 防治多种传染病。来检验我们的中心假说 为了实现我们的总体目标，我们制定了两个具体目标：1.阐明潜在的机制 炎性小体依赖的下垂通过膜修复抑制激活。基于 在这里的初步数据中，我们的工作假设是ESCRT的一个或多个调节成分 Caspase-2裂解使复合体失活。2.)确定释放出的上游机制 上睑下垂中caspase-2依赖的膜修复机制失活。

The molecular mechanism that defines whether inflammasome activation leads to cell death or survival and activation of immune cells, is unknown. Inflammasomes are protein complexes that function as cellular pathogen sensors. Upon sensing a pathogen, a member of the caspase cysteine protease family, caspase-1 is activated in inflammasomes. Active caspase-1 cleaves gasdermin-D (GSDMD), that subsequently forms pores throughout the plasma membrane leading to a form of cell death named pyroptosis. Paradoxically, the formation of GSDMD pores on the plasma membrane does not always lead to pyroptosis. It has been described that the endosomal sorting complex required for transport (ESCRT) results in membrane repair. It is not known what are the upstream signals which determine whether damaged membranes are repaired or not. It is an important problem, because without understanding this, the beneficial part of inflammasome activation (cytokine maturation) cannot be uncoupled from the detrimental and highly inflammatory pyroptosis. Based on our preliminary data, our hypothesis is that the ESCRT complex is inactivated via protease cleavage by caspase-2, which promotes pyroptosis. This hypothesis is supported by our preliminary work in which bacterial pore forming toxins trigger the pathogen detection response and stimulate inflammasomes. In this system, caspase-2 interacts with and cleaves the ESCRT associated protein ALIX. The rationale for the research is that, understanding this novel regulation of inflammasome driven pyroptosis could lead to new and innovative approaches to the prevention and treatment of a variety of infectious diseases. To test our central hypothesis and accomplish our overall objective, we formulated two specific aims: 1.) Elucidate the mechanism underlying the inflammasome dependent pyroptosis activation via membrane repair inhibition. Based on the preliminary data herein, our working hypothesis is that one or more regulatory components of ESCRT complex are inactivated by caspase-2 cleavage. 2.) Identify the upstream mechanisms that unleash caspase-2 dependent inactivation of membrane repair mechanisms in pyroptosis.