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)是人类细胞内的一个主要隔室，对于确保蛋白质保持其正确的形状非常重要，特别是分泌蛋白质，如抗体和激素。突然产生大量分泌蛋白质的需求可能会压倒内质网正确维持蛋白质结构的能力，这可能导致神经疾病和癌症。启动一个整流信号，增强内质网维持蛋白质动态平衡的能力。应激受体IRE1是这一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，我们的目标是了解IRE1是如何在内质网中错误折叠的蛋白质增加导致UPR的情况下被激活的。此外，我们的目标是可视化IRE1的3D形状，以便进一步深入了解信号激活。因此，该提议将对IRE1机制产生新的见解，从而更好地理解如何在疾病中靶向IRE1信号转导。