INSERM U1053, Bordeaux, France.
Am J Physiol Cell Physiol. 2013 Jun 15;304(12):C1117-26. doi: 10.1152/ajpcell.00061.2013. Epub 2013 Mar 20.
The endoplasmic reticulum (ER)-induced unfolded protein response (ERUPR) is an adaptive mechanism that is activated upon accumulation of misfolded proteins in the ER and aims at restoring ER homeostasis. The ERUPR is transduced by three major ER-resident stress sensors, namely PKR-like endoplasmic reticulum kinase (PERK), activating transcription factor 6 (ATF6), and inositol requiring enzyme 1 (IRE1). Activation of these ER stress sensors leads to transcriptional reprogramming of the cells. Recently, microRNAs (miRNAs), small noncoding RNAs that generally repress gene expression, have emerged as key regulators of ER homeostasis and important players in ERUPR-dependent signaling. Moreover, the miRNAs biogenesis machinery appears to also be regulated upon ER stress. Herein we extensively review the relationships existing between "canonical" ERUPR signaling, control of ER homeostasis, and miRNAs. We reveal an intricate signaling network that might confer specificity and selectivity to the ERUPR in tissue- or stress-dependent fashion. We discuss these issues in the context of the physiological and pathophysiological roles of ERUPR signaling.
内质网（ER）诱导的未折叠蛋白反应（ERUPR）是一种适应性机制，当 ER 中错误折叠的蛋白质积累时会被激活，旨在恢复 ER 稳态。ERUPR 通过三种主要的 ER 驻留应激传感器转导，即蛋白激酶 R 样内质网激酶（PERK）、激活转录因子 6（ATF6）和肌醇需求酶 1（IRE1）。这些 ER 应激传感器的激活导致细胞的转录重编程。最近，微小 RNA（miRNA），即通常抑制基因表达的小非编码 RNA，已成为 ER 稳态的关键调节剂和 ERUPR 依赖性信号转导的重要参与者。此外，miRNA 生物发生机制似乎也受到 ER 应激的调节。本文我们广泛综述了“经典”ERUPR 信号、ER 稳态控制与 miRNAs 之间的关系。我们揭示了一个复杂的信号网络，该网络可能以组织或应激依赖的方式赋予 ERUPR 特异性和选择性。我们在 ERUPR 信号转导的生理和病理生理作用的背景下讨论了这些问题。
