Unfolded protein response (UPR) integrated signaling networks determine cell fate during hypoxia

Bartoszewska, Sylwia; Collawn, James F.

doi:10.1186/s11658-020-00212-1

Cited by 92 publications

(87 citation statements)

References 276 publications

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“…Both the increased ER membrane and the protein folding demand can result in coronavirus-related ER stress and activation of a dedicated signaling pathway, the unfolded protein response (UPR). Importantly, the UPR has the ability to promote cellular survival by increasing ER membranes and folding capacity, but also has the ability to induce cell death if the stress is persistent ( 5 , 8 , 10 , 37 , 45 , 51 , 104 ).…”

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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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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“…The activation of this pathway protects the cell against protein misfolding during hypoxia [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ]. Despite the importance of both HIFs and the UPR pathway for the cancer microenvironment and cardiovascular disorders, the relationship between the HIFs and the UPR is poorly understood, especially in the normal human endothelium [ 12 ]. Although the HIF-dependent activation of the PERK axes has been reported in both cancer and normal cells [ 4 , 13 ], the hypoxic activation of ATF6 and IRE1 signaling remains ambiguous.…”

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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“…It has been reported that in severe cases of COVID-19, hypoxaemia is induced by the pneumonic process and might have several adverse effects in patients (Rello et al, 2020). There are several lines of defence mechanisms in response to hypoxia, which is a consequence of hypoxaemia, including responses triggers from mitochondria and ER (Bartoszewska and Collawn, 2020). The main goal of these responses to hypoxia is restoring oxygen level and promoting cell survival in these conditions (Bartoszewska and Collawn, 2020).…”

Section: Opinionmentioning

confidence: 99%

“…There are several lines of defence mechanisms in response to hypoxia, which is a consequence of hypoxaemia, including responses triggers from mitochondria and ER (Bartoszewska and Collawn, 2020). The main goal of these responses to hypoxia is restoring oxygen level and promoting cell survival in these conditions (Bartoszewska and Collawn, 2020). Therefore, in prolonged hypoxia induction via COVID-19, the UPR is triggered to help the cells to survive.…”

Section: Opinionmentioning

confidence: 99%

Endoplasmic reticulum as a potential therapeutic target for covid-19 infection management?

Sureda

Alizadeh

Nabavi

et al. 2020

European Journal of Pharmacology

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Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre-including this research content-immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

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Unfolded protein response (UPR) integrated signaling networks determine cell fate during hypoxia

Cited by 92 publications

References 276 publications

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

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

Endoplasmic reticulum as a potential therapeutic target for covid-19 infection management?

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