Experimental reconstitution of chronic ER stress in the liver reveals feedback suppression of BiP mRNA expression
Experimental reconstitution of chronic ER stress in the liver reveals feedback suppression of BiP mRNA expression
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DOI：
10.7554/elife.20390
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发表时间：
2016-12-10
期刊：
影响因子：
7.7
通讯作者：
Rutkowski, D. Thomas
中科院分区：
文献类型：
--
作者：
Gomez, Javier A.;Rutkowski, D. Thomas
内质网（ER）应激与许多慢性疾病有关，但关于未折叠蛋白反应（UPR）如何在体内对持续的内质网应激作出反应，我们知之甚少。在这里，我们通过反复注射低剂量的内质网应激源tunicamycin，实验性地重建了小鼠肝脏中的慢性内质网应激。矛盾的是，这种治疗导致了反馈介导的一组精选mrna的抑制，包括编码ER伴侣BiP和GRP94的mrna。这种抑制是由于upr依赖转录的ATF6a途径的沉默和mRNA降解的增强，可能是通过受调节的ire1依赖衰变（RIDD）。BiP蛋白异位过表达对编码BiP的mRNA的抑制，在肥胖小鼠中也有观察到。我们的研究结果表明，持续的UPR激活和失活周期为UPR依赖的转录调控创造了一个改变的、准稳定的设定值，这一结果可能与代谢综合征等疾病有关。
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 ATF6a 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 regulationan outcome that could be relevant to conditions such as metabolic syndrome.