Endoplasmic reticulum (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.
The MRC Laboratory of Molecular Biology (LMB) has long been, and remains, a world-class research laboratory. Our primary goal is to understand biological processes at the molecular level, through the application of methods drawn from physics, chemistry and genetics. This quest extends from structural studies of individual macromolecules, through their interactions and beyond to the functioning of subcellular systems, cells and multicellular systems in whole organisms, with the ultimate aim of using this knowledge to tackle specific problems in human health and disease. The LMB is one of the birthplaces of modern molecular biology. Many techniques were pioneered at the laboratory, most notably methods for determining the three-dimensional structure of proteins and DNA sequencing. Whole genome sequencing was initiated at the LMB. Another landmark discovery was the invention of monoclonal antibodies. Over the years, the work of LMB scientists has attracted 9 Nobel Prizes, shared between 13 LMB scientists, as well as numerous other prizes and scientific awards.
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