Investigation of IRE1a Regulatory Mechanism
Lead Research Organisation:
University of Cambridge
Department Name: Cambridge Institute for Medical Research
Abstract
The unfolded protein response (UPR) defends protein folding homeostasis in the endoplasmic reticulum (ER) by matching the folding capacity to the unfolded protein load. This simple feedback process impacts the function of the secretory pathway and because protein secretion is central to intercellular communication, ER stress and the response to it influences many physiological and pathophysiological processes. It is widely accepted that the key UPR transducer, IRE1 responds to the unfolded protein burden by dimerization-dependent activation, however the molecular basis of this upstream event in the UPR remains poorly understood. Recently the Ron lab has uncovered evidence for a regulatory mechanism whereby an ER luminal co-chaperone ERdj4 directs the ER Hsp70 BiP to repress IRE1 by binding its luminal domain. As unfolded proteins compete for BiP, IRE1 activity is governed by the balance between BiP and unfolded ER proteins. Though supported by genetic and biochemical observations, structural information on regions of IRE1 involved in the kinetically maintained, BiP-induced repressive event is lacking. Also lacking is insight into the changes IRE1 undergoes upon BiP binding and the reverse mechanism of BiP dissociation and its regulation. With this project I hope to deepen our understanding of the fundaments of IRE1 regulation which may one day pave the way for pharmacological intervention in UPR signalling, a goal of relevance to health and biotechnology.
Organisations
People |
ORCID iD |
David Ron (Primary Supervisor) | |
Lisa Neidhardt (Student) |
Studentship Projects
Project Reference | Relationship | Related To | Start | End | Student Name |
---|---|---|---|---|---|
MR/N013433/1 | 01/10/2016 | 30/04/2026 | |||
2304568 | Studentship | MR/N013433/1 | 01/10/2019 | 31/03/2023 | Lisa Neidhardt |