Ratiometric sensing of BiP-client versus BiP levels by the unfolded protein response determines its signaling amplitude
- San Raffaele Scientific Institute, Italy
- FIRC Institute of Molecular Oncology, Italy
Abstract
Insufficient folding capacity of the endoplasmic reticulum (ER) activates the unfolded protein response (UPR) to restore homeostasis. Yet, how the UPR achieves ER homeostatic readjustment is poorly investigated, since in most studies the ER-stress that is elicited cannot be overcome. Here we show that a proteostatic insult, achieved by persistent expression of the secretory heavy chain of immunoglobulin M (µs), is well-tolerated in HeLa cells. Upon µs expression, its levels temporarily eclipse those of the ER-chaperone BiP, leading to acute, full-geared UPR activation. Once BiP is in excess again, the UPR transitions to chronic, submaximal activation, indicating that the UPR senses ER-stress in a ratiometric fashion. In the process the ER expands about threefold and becomes dominated by BiP. Since the UPR is essential for successful ER homeostatic readjustment in the HeLa-µs model, it provides an ideal system for dissecting the intricacies of how the UPR evaluates and alleviates ER-stress.
Article and author information
Author details
Funding
Giovanni Armenise-Harvard Foundation
- Eelco van Anken
Ministero della Salute (RF - 2011-02352852)
- Eelco van Anken
Associazione Italiana per la Ricerca sul Cancro (MFAG 13584)
- Eelco van Anken
Ministero della Salute (PE-2011-02352286)
- Roberto Sitia
- Eelco van Anken
Associazione Italiana per la Ricerca sul Cancro (IG 2016-18824)
- Roberto Sitia
Fondazione Telethon (GGP15059)
- Roberto Sitia
Fondazione Cariplo (2015-0591)
- Roberto Sitia
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Davis Ng, Temasek Life Sciences Laboratory and National University of Singapore, Singapore
Version history
- Received: April 6, 2017
- Accepted: December 15, 2017
- Accepted Manuscript published: December 18, 2017 (version 1)
- Version of Record published: January 31, 2018 (version 2)
Copyright
© 2017, Bakunts et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Ratiometric sensing of BiP-client versus BiP levels by the unfolded protein response determines its signaling amplitude
eLife 6:e27518.
https://doi.org/10.7554/eLife.27518
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