Experimental reconstitution of chronic ER stress in the liver reveals feedback suppression of BiP mRNA expression

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Abstract

ER stress is implicated in many chronic diseases, but very little is known about how the unfolded protein response (UPR) responds to persistent ER stress in vivo. Here, we experimentally reconstituted chronic ER stress in the mouse liver, using repeated injection of a low dose of the ER stressor tunicamycin. Paradoxically, this treatment led to feedback-mediated suppression of a select group of mRNAs, including those encoding the ER chaperones BiP and GRP94. This suppression was due to both silencing of the ATF6α pathway of UPR-dependent transcription and enhancement of mRNA degradation, possibly via regulated IRE1-dependent decay (RIDD). The suppression of mRNA encoding BiP was phenocopied by ectopic overexpression of BiP protein, and was also observed in obese mice. Our findings suggest that persistent cycles of UPR activation and deactivation create an altered, quasi-stable setpoint for UPR-dependent transcriptional regulation-an outcome that could be relevant to conditions such as metabolic syndrome.

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Javier A Gomez

Graduate Program in Molecular and Cellular Biology, University of Iowa Carver College of Medicine, Iowa City, United States

Competing interests
The authors declare that no competing interests exist.
D Thomas Rutkowski

Departments of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, United States

For correspondence
thomas-rutkowski@uiowa.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-6586-4449

Funding

National Institute of General Medical Sciences (GM115424)

D Thomas Rutkowski

National Institute of General Medical Sciences (GM067795)

Javier A Gomez

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All protocols for animal use, including euthanasia and miminzation of distress, were reviewed and approved by the University Committee on Use and Care of Animals at the University of Iowa, protocol number 4061076.

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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.