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

Bartoszewska, Sylwia; Cabaj, Aleksandra; Dąbrowski, Michał; Collawn, James F.; Bartoszewski, Rafał

doi:10.1096/fj.201900600rr

Cited by 36 publications

(41 citation statements)

References 69 publications

(66 reference statements)

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“…The resulting frame shift in the coding region of the XBP1 mRNA gives rise to the active XBP1s form, which functions as a transcription factor for UPR-associated genes [ 29 ]. Posttranscriptional regulation of the XBP1 mRNA has been previously reported for different miRNAs, leading to similar functional effects as shown by our results [ 30 , 31 ]. Here, we report that miR-34a directly targets the IRE1α branch of the UPR by regulating the two key components, XBP1 and IRE1α, underlining a more complex regulatory network.…”

Section: Discussionsupporting

confidence: 91%

Induction of the Endoplasmic-Reticulum-Stress Response: MicroRNA-34a Targeting of the IRE1α-Branch

Krammes

Hart

Rheinheimer

et al. 2020

Cells

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Neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) are characterized by the accumulation of misfolded proteins in the endoplasmic reticulum (ER) and the unfolded protein response (UPR). Modulating the UPR is one of the major challenges to counteract the development of neurodegenerative disorders and other diseases with affected UPR. Here, we show that miR-34a-5p directly targets the IRE1α branch of the UPR, including the genes BIP, IRE1α, and XBP1. Upon induction of ER stress in neuronal cells, miR-34a-5p overexpression impacts the resulting UPR via a significant reduction in IRE1α and XBP1s that in turn leads to decreased viability, increased cytotoxicity and caspase activity. The possibility to modify the UPR signaling pathway by a single miRNA that targets central genes of the IRE1α branch offers new perspectives for future therapeutic approaches against neurodegeneration.

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Section: Discussionsupporting

confidence: 91%

Induction of the Endoplasmic-Reticulum-Stress Response: MicroRNA-34a Targeting of the IRE1α-Branch

Krammes

Hart

Rheinheimer

et al. 2020

Cells

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“…IRE1α uses its endoribonuclease properties to selectively reduce ER mRNA ( 40 , 72 ) and to produce the active isoform of the X-box binding protein transcription factor (XBP1s) ( 118 ). XBP1s increases the ER’s folding capacity and ER membrane biosynthesis, as well as vesicular trafficking ( 4 , 7 , 118 ). XBP1s can also lead to decreased antigen presentation ( 7 ).…”

Section: Comparison Of the Mirna Target Sites In Human Coronavirusesmentioning

confidence: 99%

SARS-CoV-2 may regulate cellular responses through depletion of specific host miRNAs

Bartoszewski

Dąbrowski

Jakieła

et al. 2020

American Journal of Physiology-Lung Cellular and Molecular Phys

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Cold viruses have generally been considered fairly innocuous until the appearance of the severe acute respiratory coronavirus 2 (SARS-CoV-2) in 2019 which caused the coronavirus disease 2019 (COVID-19) global pandemic. Two previous viruses foreshadowed that a coronavirus could potentially have devastating consequences in 2002 (severe acute respiratory coronavirus (SARS-CoV)) and in 2012 (middle east respiratory syndrome coronavirus (MERS-CoV)). The question that arises is why these viruses are so different from the relatively harmless cold viruses. Based on an analysis of the current literature and using bioinformatic approaches, we examined the potential human miRNA interactions with the SARS-CoV-2's genome, and compared the miRNA target sites in seven coronavirus genomes that include SARS-CoV-2, MERS-CoV, SARS-CoV, and four non-pathogenic coronaviruses. Here, we discuss the possibility that pathogenic HCoVs including SARS-CoV-2 could modulate host miRNA levels by acting as miRNA sponges to facilitate viral replication and/or to avoid immune responses.

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“…The activation of IRE1α leads to the reduction of protein synthesis through regulated IRE1-dependent decay (RIDD), which results in the degradation of selected mRNAs [ 14 ]. Additionally, the active spliced isoform of the X-box binding-protein transcription factor (XBP1s) is formed by the endoribonuclease activity of IRE1α [ 15 ], facilitating cell survival and increasing the ER’s folding capacity [ 15 , 16 , 17 ]. Furthermore, the inflammatory response and activation of autophagy and apoptosis processes led by Janus N-terminal kinase (JNK) is achieved by IRE1α kinase activity [ 14 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

IRE1 Endoribonuclease Activity Modulates Hypoxic HIF-1α Signaling in Human Endothelial Cells

2020

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While the role of hypoxia and the induction of the hypoxia inducible factors (HIFs) and the unfolded protein response (UPR) pathways in the cancer microenvironment are well characterized, their roles and relationship in normal human endothelium are less clear. Here, we examined the effects of IRE1 on HIF-1α protein levels during hypoxia in primary human umbilical vein endothelial cells (HUVECs). The results demonstrated that HIF-1α levels peaked at 6 h of hypoxia along with two of their target genes, GLUT1 and VEGFA, whereas at up to 12 h of hypoxia the mRNA levels of markers of the UPR, IRE1, XBP1s, BiP, and CHOP, did not increase, suggesting that the UPR was not activated. Interestingly, the siRNA knockdown of IRE1 or inhibition of IRE1 endonuclease activity with 4µ8C during hypoxia significantly reduced HIF-1α protein without affecting HIF1A mRNA expression. The inhibition of the endonuclease activity with 4µ8C in two other primary endothelial cells during hypoxia, human cardiac microvascular endothelial cells and human aortic endothelial cells showed the same reduction in the HIF-1α protein. Surprisingly, the siRNA knockdown of XBP1s during hypoxia did not decrease the HIF1α protein levels, indicating that the IRE1-mediated effect on stabilizing the HIF1α protein levels was XBP1s-independent. The studies presented here, therefore, provide evidence that IRE1 activity during hypoxia increases the protein levels of HIF1α in an XBP1s-independent manner.

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

Cited by 36 publications

References 69 publications

Induction of the Endoplasmic-Reticulum-Stress Response: MicroRNA-34a Targeting of the IRE1α-Branch

Induction of the Endoplasmic-Reticulum-Stress Response: MicroRNA-34a Targeting of the IRE1α-Branch

SARS-CoV-2 may regulate cellular responses through depletion of specific host miRNAs

IRE1 Endoribonuclease Activity Modulates Hypoxic HIF-1α Signaling in Human Endothelial Cells

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