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Enteroviruses Manipulate the Unfolded Protein Response through Multifaceted Deregulation of the Ire1-Xbp1 Pathway

Many viruses are known to trigger endoplasmic reticulum (ER) stress in host cells, which in turn can develop a protective unfolded protein response (UPR). Depending on the conditions, the UPR may lead to either cell survival or programmed cell death. One of three UPR branches involves the upregulati...

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Autores principales: Shishova, Anna, Dyugay, Ilya, Fominykh, Ksenia, Baryshnikova, Victoria, Dereventsova, Alena, Turchenko, Yuriy, Slavokhotova, Anna A., Ivin, Yury, Dmitriev, Sergey E., Gmyl, Anatoly
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9699254/
https://www.ncbi.nlm.nih.gov/pubmed/36366584
http://dx.doi.org/10.3390/v14112486
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author Shishova, Anna
Dyugay, Ilya
Fominykh, Ksenia
Baryshnikova, Victoria
Dereventsova, Alena
Turchenko, Yuriy
Slavokhotova, Anna A.
Ivin, Yury
Dmitriev, Sergey E.
Gmyl, Anatoly
author_facet Shishova, Anna
Dyugay, Ilya
Fominykh, Ksenia
Baryshnikova, Victoria
Dereventsova, Alena
Turchenko, Yuriy
Slavokhotova, Anna A.
Ivin, Yury
Dmitriev, Sergey E.
Gmyl, Anatoly
author_sort Shishova, Anna
collection PubMed
description Many viruses are known to trigger endoplasmic reticulum (ER) stress in host cells, which in turn can develop a protective unfolded protein response (UPR). Depending on the conditions, the UPR may lead to either cell survival or programmed cell death. One of three UPR branches involves the upregulation of Xbp1 transcription factor caused by the unconventional cytoplasmic splicing of its mRNA. This process is accomplished by the phosphorylated form of the endoribonuclease/protein kinase Ire1/ERN1. Here, we show that the phosphorylation of Ire1 is up-regulated in HeLa cells early in enterovirus infection but down-regulated at later stages. We also find that Ire1 is cleaved in poliovirus- and coxsackievirus-infected HeLa cells 4–6 h after infection. We further show that the Ire1-mediated Xbp1 mRNA splicing is repressed in infected cells in a time-dependent manner. Thus, our results demonstrate the ability of enteroviruses to actively modulate the Ire1-Xbp1 host defensive pathway by inducing phosphorylation and proteolytic cleavage of the ER stress sensor Ire1, as well as down-regulating its splicing activity. Inactivation of Ire1 could be a novel mode of the UPR manipulation employed by viruses to modify the ER stress response in the infected cells.
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spelling pubmed-96992542022-11-26 Enteroviruses Manipulate the Unfolded Protein Response through Multifaceted Deregulation of the Ire1-Xbp1 Pathway Shishova, Anna Dyugay, Ilya Fominykh, Ksenia Baryshnikova, Victoria Dereventsova, Alena Turchenko, Yuriy Slavokhotova, Anna A. Ivin, Yury Dmitriev, Sergey E. Gmyl, Anatoly Viruses Article Many viruses are known to trigger endoplasmic reticulum (ER) stress in host cells, which in turn can develop a protective unfolded protein response (UPR). Depending on the conditions, the UPR may lead to either cell survival or programmed cell death. One of three UPR branches involves the upregulation of Xbp1 transcription factor caused by the unconventional cytoplasmic splicing of its mRNA. This process is accomplished by the phosphorylated form of the endoribonuclease/protein kinase Ire1/ERN1. Here, we show that the phosphorylation of Ire1 is up-regulated in HeLa cells early in enterovirus infection but down-regulated at later stages. We also find that Ire1 is cleaved in poliovirus- and coxsackievirus-infected HeLa cells 4–6 h after infection. We further show that the Ire1-mediated Xbp1 mRNA splicing is repressed in infected cells in a time-dependent manner. Thus, our results demonstrate the ability of enteroviruses to actively modulate the Ire1-Xbp1 host defensive pathway by inducing phosphorylation and proteolytic cleavage of the ER stress sensor Ire1, as well as down-regulating its splicing activity. Inactivation of Ire1 could be a novel mode of the UPR manipulation employed by viruses to modify the ER stress response in the infected cells. MDPI 2022-11-10 /pmc/articles/PMC9699254/ /pubmed/36366584 http://dx.doi.org/10.3390/v14112486 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Shishova, Anna
Dyugay, Ilya
Fominykh, Ksenia
Baryshnikova, Victoria
Dereventsova, Alena
Turchenko, Yuriy
Slavokhotova, Anna A.
Ivin, Yury
Dmitriev, Sergey E.
Gmyl, Anatoly
Enteroviruses Manipulate the Unfolded Protein Response through Multifaceted Deregulation of the Ire1-Xbp1 Pathway
title Enteroviruses Manipulate the Unfolded Protein Response through Multifaceted Deregulation of the Ire1-Xbp1 Pathway
title_full Enteroviruses Manipulate the Unfolded Protein Response through Multifaceted Deregulation of the Ire1-Xbp1 Pathway
title_fullStr Enteroviruses Manipulate the Unfolded Protein Response through Multifaceted Deregulation of the Ire1-Xbp1 Pathway
title_full_unstemmed Enteroviruses Manipulate the Unfolded Protein Response through Multifaceted Deregulation of the Ire1-Xbp1 Pathway
title_short Enteroviruses Manipulate the Unfolded Protein Response through Multifaceted Deregulation of the Ire1-Xbp1 Pathway
title_sort enteroviruses manipulate the unfolded protein response through multifaceted deregulation of the ire1-xbp1 pathway
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9699254/
https://www.ncbi.nlm.nih.gov/pubmed/36366584
http://dx.doi.org/10.3390/v14112486
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