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

Moszyńska, Adrianna; Collawn, James F.; Bartoszewski, Rafał

doi:10.3390/biom10060895

Cited by 24 publications

(16 citation statements)

References 65 publications

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“…Upregulation of CHOP mRNA was also found in our study after TM or BFA treatment of ACH-3P cells, whereas low oxygen tension decreased CHOP expression. This contrasts to results obtained in other cell types such as endothelial and neuronal cells (Tajiri et al 2004, Moszyńska et al 2020, in which ischemia, that is, low oxygen, induces CHOP expression and cell death. Thus, CHOP downregulation in early pregnancy might ensure trophoblast cell survival allowing placental development under adverse environmental conditions in utero.…”

Section: Discussioncontrasting

confidence: 99%

Different regulation of IRE1α and eIF2α pathways by oxygen and insulin in ACH-3P trophoblast model

et al. 2021

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Endoplasmic reticulum (ER)-stress activates the unfolded protein response (UPR), which plays a (patho)physiological role in the placenta. Oxygen and hyperinsulinemia are major regulators of placental development. Thus, we hypothesized that oxygen, insulin and their interplay modulate ER-stress in early pregnancy. Using the human first-trimester trophoblast cell line ACH-3P, we quantified mRNA and protein of several members of UPR by RT-qPCR and Western blotting, respectively. ER-stress induction using tunicamycin and brefeldin A resulted in increased CHOP (4.6-fold change; P ≤ 0.001), XBP1 expression (1.7- and 1.3-fold change, respectively; P ≤ 0.001 and P < 0.05) and XBP1 splicing (7.9- and 12.8-fold change, respectively; P ≤ 0.001). We subsequently analyzed the effect of oxygen (6.5%, 2.5%), insulin (0.1–10 nM) and their interaction using ANCOVA adjusted for cell passage as co-variate. Although GRP78 protein remained unaffected, low oxygen (2.5% O2) increased IRE1α phosphorylation (+52%; P < 0.05) and XBP1 splicing (1.8-fold change; P ≤ 0.001) after 24 h, while eIF2α protein and CHOP expression were downregulated (−28%; P < 0.05 and −24%; P ≤ 0.001; respectively). eIF2α phosphorylation was also reduced after 48 h by low oxygen (−61%; P < 0.05) but increased in the presence of insulin (+46%; P ≤ 0.01). These changes were not PERK-mediated, since PERK phosphorylation and total protein were not altered. Overall, our results suggest that IRE1α and eIF2α UPR-pathways are differentially regulated by oxygen and insulin in early pregnancy.

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Section: Discussioncontrasting

confidence: 99%

Different regulation of IRE1α and eIF2α pathways by oxygen and insulin in ACH-3P trophoblast model

et al. 2021

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“…If the stress is persistent, PERK and ATF6 induce cell death via accumulation of CCAAT/enhancer binding homologous protein (CHOP) ( 2 , 8 , 49 , 80 ). 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 ).…”

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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“…Based on these results, we next tested whether the decrease in XBP1s was due to a inhibition of IRE1α endoribonuclease activity. We compared the C-1305 effectiveness in preventing IRE1α-dependent XBP1 mRNA splicing with the efficiency of commonly used IRE1 inhibitor 4µ8C [ 35 , 48 ] (Fig. 4 a).…”

Section: Resultsmentioning

confidence: 99%

Triazoloacridone C-1305 impairs XBP1 splicing by acting as a potential IRE1α endoribonuclease inhibitor

et al. 2021

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Inositol requiring enzyme 1 alpha (IRE1α) is one of three signaling sensors in the unfolding protein response (UPR) that alleviates endoplasmic reticulum (ER) stress in cells and functions to promote cell survival. During conditions of irrevocable stress, proapoptotic gene expression is induced to promote cell death. One of the three signaling stressors, IRE1α is an serine/threonine-protein kinase/endoribonuclease (RNase) that promotes nonconventional splicing of XBP1 mRNA that is translated to spliced XBP1 (XBP1s), an active prosurvival transcription factor. Interestingly, elevated IRE1α and XBP1s are both associated with poor cancer survival and drug resistance. In this study, we used next-generation sequencing analyses to demonstrate that triazoloacridone C-1305, a microtubule stabilizing agent that also has topoisomerase II inhibitory activity, dramatically decreases XBP1s mRNA levels and protein production during ER stress conditions, suggesting that C-1305 does this by decreasing IRE1α’s endonuclease activity.

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

Cited by 24 publications

References 65 publications

Different regulation of IRE1α and eIF2α pathways by oxygen and insulin in ACH-3P trophoblast model

Different regulation of IRE1α and eIF2α pathways by oxygen and insulin in ACH-3P trophoblast model

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

Triazoloacridone C-1305 impairs XBP1 splicing by acting as a potential IRE1α endoribonuclease inhibitor

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