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

内质网（ER）是人类细胞内的一个主要区室，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。突然需要产生大量的分泌蛋白质会使内质网无法正确维持蛋白质结构，从而导致神经系统疾病和癌症。启动整流信号，增强ER维持蛋白质稳态的能力。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，我们的目标是利用纯化的蛋白质和基于生物化学、细胞和结构的方法，了解IRE1是如何被激活的，以响应ER内错误折叠的蛋白质的增加，从而导致UPR。此外，我们的目标是可视化IRE1的3D形状，以促进对信号激活的进一步了解。因此，该提案将产生对IRE1机制的新见解，以更好地了解如何靶向IRE1信号转导疾病。

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.