ER stress signalling by the UPR activator IRE1 and its regulation by BiP

UPR 激活剂 IRE1 的内质网应激信号传导及其 BiP 的调节

• 批准号: MR/Y012224/1
• 负责人: Maruf Ali
• 金额: $ 77.19万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY012224%2F1
• 关键词: ER; stress; signalling; UPR; activator

The Endoplasmic Reticulum (ER) is a major compartment within the human cell that is important for ensuring proteinsattain their correct shape, particularly secretory proteins such as antibodies and hormones. The sudden requirement toproduce large quantities of secretory proteins can overwhelm the ER's capacity to correctly maintain protein structure,which can result in neurological diseases andcancer. A rectifying signal is initiated that bolsters the ER's capacity to maintain protein homeostasis. The stress receptorIRE1 is a critical component of this process. However, the molecular details of IRE1 signal activation are not clearlyunderstood.Using purified proteins and a biochemical, cellular and structural based approach, we aim to understand how IRE1 is activated inresponse to an increase in misfolded protein within the ER that leads to UPR Furthermore, we aim to visualise the 3D shape of IRE1 facilitating further insights into signal activation. Thus, the proposalwill generate novel insights into IRE1 mechanism towards providing a better understanding of how to target IRE1 signallingin disease.

内质网 (ER) 是人体细胞内的一个主要区室，对于确保蛋白质（尤其是抗体和激素等分泌蛋白）保持正确的形状非常重要。突然需要产生大量分泌蛋白可能会超出内质网正确维持蛋白质结构的能力，从而导致神经系统疾病和癌症。整流信号的启动增强了内质网维持蛋白质稳态的能力。压力感受器IRE1是这个过程的关键组成部分。然而，IRE1 信号激活的分子细节尚不清楚。使用纯化的蛋白质和基于生化、细胞和结构的方法，我们旨在了解 IRE1 是如何被激活以响应 ER 内错误折叠蛋白质的增加而导致 UPR 此外，我们的目标是可视化 IRE1 的 3D 形状，以促进进一步了解信号激活。因此，该提案将对 IRE1 机制产生新的见解，从而更好地理解如何针对 IRE1 信号传导疾病。