Experimental Reconstitution of Chronic ER Stress in the Liver Reveals Feedback Suppression of Bip mRNA Expression

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 ATF6a pathway of UPR-dependent transcription and enhancement of mRNA degradation, most likely via regulated IRE1-dependent decay (RIDD). The suppression of Bip mRNA was phenocopied by ect