Abstract
Author SummarySecreted and membrane-spanning proteins constitute one of every three proteins produced by a eukaryotic cell. Many of these proteins initially fold and assemble in the endoplasmic reticulum (ER). A variety of physiological and environmental conditions can increase the demands on the ER, overwhelming the ER protein folding machinery. To restore homeostasis in response to ER stress, cells activate an intracellular signaling pathway called the unfolded protein response (UPR) that adjusts the folding capacity of the ER according to need. Its failure impairs cell viability and has been implicated in numerous disease states. In this study, we quantitatively interrogate the homeostatic capacity of the UPR. We arrive at a mechanistic model for how the ER stress sensor Ire1 cooperates with its binding partner BiP, a highly redundant ER chaperone, to fine-tune UPR activity. Moving between a predictive computational model and experiments, we show that BiP release from Ire1 is not the switch that activates Ire1; rather, BiP modulates Ire1 activation and deactivation dynamics. BiP binding to Ire1 and its dissociation in an ER stress-dependent manner buffers the system against mild stresses. Furthermore, BiP binding accelerates Ire1 deactivation when stress is removed. We conclude that BiP binding to Ire1 serves to fine-tune the dynamic behavior of the UPR by modulating its sensitivity and shutoff kinetics. This function of the interaction between Ire1 and BiP may be a general paradigm for other systems in which oligomer formation and disassembly must be finely regulated.
Highlights
The secreted and membrane-spanning proteins that eukaryotic cells use to sense and respond to their environments and to communicate with other cells are functional only when they attain their proper three-dimensional structures
To restore homeostasis in response to endoplasmic reticulum (ER) stress, cells activate an intracellular signaling pathway called the unfolded protein response (UPR) that adjusts the folding capacity of the ER according to need
We arrive at a mechanistic model for how the ER stress sensor Ire1 cooperates with its binding partner BiP, a highly redundant ER chaperone, to fine-tune UPR activity
Summary
The secreted and membrane-spanning proteins that eukaryotic cells use to sense and respond to their environments and to communicate with other cells are functional only when they attain their proper three-dimensional structures. When cells experience environmental stresses, nutrient depletion, or certain differentiation cues, the ER folding and degradation machineries can become overwhelmed and the cell risks accumulating and secreting malfunctional and potentially harmful proteins [1]. Such conditions of ER stress activate the unfolded protein response (UPR) [2], resulting in an expanded ER [3,4] and increased expression of genes encoding ER chaperones, ER associated degradation machinery, and other components of the secretory pathway [5]. The UPR provides a feedback loop that helps cells maintain high fidelity in protein folding and assembly
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
