Understanding how cell stress pathways contribute to defense responses in healthy cells

这项建议研究了未折叠蛋白反应(UPR)的组成部分如何有助于启动分子信号通路，以促进健康细胞的防御反应。未折叠蛋白反应(UPR)是一种高度保守的应激反应途径，通过积累未折叠或错误折叠的蛋白在细胞中激活，这种情况被称为内质网(ER)应激。UPR是由三个内质网锚定的跨膜受体(IRE1、PERK和ATF6)控制的一系列协调信号通路的统称。经典地说，这些信号机制的功能是降低未折叠蛋白质的水平，恢复内质网的动态平衡。如果这是不可能的，信号从支持生存切换到支持死亡，内质网应激诱导的细胞死亡接踵而至。我们现在开始认识到，UPR通路的组成部分也影响着维持细胞存活所必需的信号通路，包括细胞防御过程。与UPR一样，炎症也可以被视为一种旨在恢复细胞内稳态的机制。然而，在炎症的情况下，最初的触发因素(外部或内部)间接导致细胞内稳态的丧失，这是由内部机制检测到的，并导致应激反应的激活。例如，我最近的工作确定了IRE1在促进NLRP3炎症体的结构组装中的作用，NLRP3炎症体是关键的细胞防御成分。这项研究计划调查细胞应激和防御信号通路如何整合并以合作的方式工作，以确保细胞活力的维持。为此，将开发针对IRE1、PERK和ATF6的细胞报告系统，使我们能够在启动细胞防御机制后监测它们在健康细胞中的激活。利用细胞生物学技术，我们将有选择地阻断UPR的每一条手臂，并评估这对健康细胞应对内部或外部威胁的能力的结果。除了这些涉及应激和防御途径之间相互作用的更广泛的问题外，我们还将确定哪些信号途径有助于IRE1介导的炎症体调节，并评估这一途径在细胞防御反应中的重要性。这项研究计划解决了两个基本的细胞信号通路之间的相互作用，以前被认为是以独立和不同的方式发挥作用。因此，它代表了细胞生物学和免疫学交叉的一个新的新兴研究领域。从这个项目中产生的知识将极大地增强我们对健康细胞如何应对环境中的挑战的理解。

This proposal examines how components of the Unfolded Protein Response (UPR) contribute to the molecular signaling pathways initiated to facilitate defense responses in healthy cells. The unfolded protein response (UPR) is a highly conserved stress response pathway activated in cells by accumulation of unfolded or misfolded proteins, a condition referred to as Endoplasmic Reticulum (ER) stress. The UPR is the collective term given to a series of orchestrated signaling pathways controlled by three ER anchored transmembrane receptors (IRE1, PERK and ATF6). Classically, these signaling mechanisms function to reduce levels of unfolded proteins and restore ER homeostasis. If that is not possible, signaling switches from pro-survival to pro-death and ER stress-induced cell death ensues. We are now beginning to realize components of the UPR pathway also influence signaling pathways essential to maintain cell viability including cellular defense processes. Like the UPR, inflammation can also be viewed as a mechanism aimed at restoring cellular homeostasis. However, in the case of inflammation the originating triggers (external or internal) indirectly cause a loss of cellular homeostasis, which is detected by internal mechanisms and leads to the activation of stress responses. For example, my recent work has defined a role for IRE1 in promoting structural assembly of the NLRP3 inflammasome a key cellular defense component. This research program investigates how cellular stress and defense signaling pathways integrate and work in a co-operative manner to insure the maintenance of cell viability. To this end, cellular reporter systems will be developed for IRE1, PERK and ATF6 allowing us to monitor their activation in healthy cells following initiation of cellular defense mechanisms. Using cell biology techniques, we will selectively block each arm of the UPR and assess the outcome of this on the ability of healthy cells to respond to internal or external threats. In addition to these broader questions addressing the interplay between stress and defense pathways, we will determine which signaling pathways contribute to IRE1-mediated regulation of the inflammasome and assess the importance of this in cell defense responses. This research program addresses the interplay between two fundamental cellular signaling pathways previously thought to act in independent and distinct manners. As such it represents a new emerging area of research at the intersection of cell biology and immunology. Knowledge generated from this program will greatly enhance our understanding of how healthy cells respond to challenges in their environment.