Regulation of the unfolded protein response by microRNAs

Abstract

The unfolded protein response (UPR) is an adaptive response to the stress that is caused by an accumulation of misfolded proteins in the lumen of the endoplasmic reticulum (ER). It is an important component of cellular homeostasis. During ER stress, the UPR increases the protein-folding capacity of the endoplasmic reticulum to relieve the stress. Failure to recover leads to apoptosis. Specific cellular mechanisms are required for the cellular recovery phase after UPR activation. Using bioinformatics tools, we identified a number of microRNAs that are predicted to decrease the mRNA expression levels for a number of critical components of the UPR. In this review, we discuss the potential role of microRNAs as key regulators of this pathway and describe how microRNAs may play an essential role in turning off the UPR after the stress has subsided.

miR‐34c‐5p modulates X‐box–binding protein 1 (XBP1) expression during the adaptive phase of the unfolded protein response

“…Using the dedicated bioinformatical approach as described in Bartoszewska et al (15), we searched for miRNAs with potential base-pair complementarities to conserved sequences in the XBP1 mRNA 39-UTR. This analysis predicted a target site for miR-34c-5p in the XBP1 39-UTR (Fig.…”

“…Although ER stress-induced miRNAs contribute to both recovery and the apoptotic arms of UPR pathway and thus balance cell fate (15)(16)(17), the detailed mechanisms of their actions on multiple components of UPR are less clear. To date, the ER stress-inducible miRNAs were mainly considered as factors that reduce ER protein load (28,45) and thus contribute to cell survival.…”

“…Recently, microRNAs (miRNAs), through their posttranscriptional effects on multiple components of UPR, have been proposed to be important components of this pathway (reviewed in refs. [15][16][17]. XBP1 is a crucial proadaptive transcription factor and is subject to transcriptional, post-transcriptional, and post-translational control (18)(19)(20)(21)(22), suggesting that XBP1 is important in deciding cell fate in the UPR.…”

miR-200b downregulates Kruppel Like Factor 2 (KLF2) during acute hypoxia in human endothelial cells

“…We used TaqManOne-Step RT-PCR Master MixReagents (Applied Biosystems) as described previously (Bartoszewska et al, 2013; Bartoszewski et al, 2011; Bartoszewski et al, 2014) using the manufacturer’s protocol. The relative expressions were calculated using the comparative relative standard curve method (Larionov et al, 2005).…”

Duhuo Jisheng decoction inhibits endoplasmic reticulum stress in chondrocytes induced by tunicamycin through the downregulation of miR-34a

“…miRNAs regulate protein expression by degrading target mRNA or inhibiting translation, resulting in complementary matching between miRNAs and specific sites in target mRNAs (42), correlate with human disease and have a potential as therapeutic targets (43)(44)(45). Emerging evidence suggests miRNAs control the balance of pro-survival and pro-apoptotic signals by acting at different steps in each arm of the pathway to regulate ER stress (46). To identify the possible mechanisms, the expression of miR-34a was examined by RT-qPCR and results showed that miR-34a was markedly downregulated in TM-exposed chondrocytes treated with DHJSD or PBA.…”