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BiP binding to the ER-stress sensor Ire1 tunes the homeostatic behavior of the unfolded protein response

PLoS biology, 2010-07, Vol.8 (7), p.e1000415-e1000415 [Peer Reviewed Journal]

Pincus et al. 2010 ;2010 Pincus et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Pincus D, Chevalier MW, Aragón T, van Anken E, Vidal SE, et al. (2010) BiP Binding to the ER-Stress Sensor Ire1 Tunes the Homeostatic Behavior of the Unfolded Protein Response. PLoS Biol 8(7): e1000415. doi:10.1371/journal.pbio.1000415 ;ISSN: 1545-7885 ;ISSN: 1544-9173 ;EISSN: 1545-7885 ;DOI: 10.1371/journal.pbio.1000415 ;PMID: 20625545

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Title:
BiP binding to the ER-stress sensor Ire1 tunes the homeostatic behavior of the unfolded protein response
Author: Pincus, David ; Chevalier, Michael W ; Aragón, Tomás ; van Anken, Eelco ; Vidal, Simon E ; El-Samad, Hana ; Walter, Peter
Kelly, Jeffrey W.
Subjects: Biochemistry/Biomacromolecule-Ligand Interactions ; Biochemistry/Macromolecular Assemblies and Machines ; Biochemistry/Protein Folding ; Biochemistry/Theory and Simulation ; Computational Biology ; Computational Biology/Signaling Networks ; Computational Biology/Systems Biology ; Computer Simulation ; Endoplasmic Reticulum - enzymology ; Endoplasmic Reticulum - pathology ; Enzyme Activation ; Enzymes ; Experiments ; Fluorescence Resonance Energy Transfer ; Fungal Proteins - metabolism ; Homeostasis ; HSP70 Heat-Shock Proteins - metabolism ; Kinetics ; Membrane Glycoproteins - chemistry ; Membrane Glycoproteins - metabolism ; Models, Biological ; Protein Binding ; Protein folding ; Protein Structure, Quaternary ; Protein-Serine-Threonine Kinases - chemistry ; Protein-Serine-Threonine Kinases - metabolism ; Reproducibility of Results ; Saccharomyces cerevisiae - enzymology ; Saccharomyces cerevisiae Proteins - chemistry ; Saccharomyces cerevisiae Proteins - metabolism ; Stress, Physiological ; Time Factors ; Unfolded Protein Response
Is Part Of: PLoS biology, 2010-07, Vol.8 (7), p.e1000415-e1000415
Description: The unfolded protein response (UPR) is an intracellular signaling pathway that counteracts variable stresses that impair protein folding in the endoplasmic reticulum (ER). As such, the UPR is thought to be a homeostat that finely tunes ER protein folding capacity and ER abundance according to need. The mechanism by which the ER stress sensor Ire1 is activated by unfolded proteins and the role that the ER chaperone protein BiP plays in Ire1 regulation have remained unclear. Here we show that the UPR matches its output to the magnitude of the stress by regulating the duration of Ire1 signaling. BiP binding to Ire1 serves to desensitize Ire1 to low levels of stress and promotes its deactivation when favorable folding conditions are restored to the ER. We propose that, mechanistically, BiP achieves these functions by sequestering inactive Ire1 molecules, thereby providing a barrier to oligomerization and activation, and a stabilizing interaction that facilitates de-oligomerization and deactivation. Thus BiP binding to or release from Ire1 is not instrumental for switching the UPR on and off as previously posed. By contrast, BiP provides a buffer for inactive Ire1 molecules that ensures an appropriate response to restore protein folding homeostasis to the ER by modulating the sensitivity and dynamics of Ire1 activity.
Publisher: United States: Public Library of Science
Language: English
Identifier: ISSN: 1545-7885
ISSN: 1544-9173
EISSN: 1545-7885
DOI: 10.1371/journal.pbio.1000415
PMID: 20625545
Source: Open Access: DOAJ Directory of Open Access Journals
Open Access: PubMed Central
PLoS (Open access)
Geneva Foundation Free Medical Journals at publisher websites
AUTh Library subscriptions: ProQuest Central
MEDLINE

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BiP binding to the ER-stress sensor Ire1 tunes the homeostatic behavior of the unfolded protein response

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