Manipulation of the unfolded protein response: A pharmacological strategy against coronavirus infection.
Coronavirus infection induces the unfolded protein response (UPR), a cellular signalling pathway composed of three branches, triggered by unfolded proteins in the endoplasmic reticulum (ER) due to high ER load. We have used RNA sequencing and ribosome profiling to investigate holistically the transc...
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| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2021-06-01
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| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1009644 |
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| author | Liliana Echavarría-Consuegra Georgia M Cook Idoia Busnadiego Charlotte Lefèvre Sarah Keep Katherine Brown Nicole Doyle Giulia Dowgier Krzysztof Franaszek Nathan A Moore Stuart G Siddell Erica Bickerton Benjamin G Hale Andrew E Firth Ian Brierley Nerea Irigoyen |
| author_facet | Liliana Echavarría-Consuegra Georgia M Cook Idoia Busnadiego Charlotte Lefèvre Sarah Keep Katherine Brown Nicole Doyle Giulia Dowgier Krzysztof Franaszek Nathan A Moore Stuart G Siddell Erica Bickerton Benjamin G Hale Andrew E Firth Ian Brierley Nerea Irigoyen |
| author_sort | Liliana Echavarría-Consuegra |
| collection | DOAJ |
| description | Coronavirus infection induces the unfolded protein response (UPR), a cellular signalling pathway composed of three branches, triggered by unfolded proteins in the endoplasmic reticulum (ER) due to high ER load. We have used RNA sequencing and ribosome profiling to investigate holistically the transcriptional and translational response to cellular infection by murine hepatitis virus (MHV), often used as a model for the Betacoronavirus genus to which the recently emerged SARS-CoV-2 also belongs. We found the UPR to be amongst the most significantly up-regulated pathways in response to MHV infection. To confirm and extend these observations, we show experimentally the induction of all three branches of the UPR in both MHV- and SARS-CoV-2-infected cells. Over-expression of the SARS-CoV-2 ORF8 or S proteins alone is itself sufficient to induce the UPR. Remarkably, pharmacological inhibition of the UPR greatly reduced the replication of both MHV and SARS-CoV-2, revealing the importance of this pathway for successful coronavirus replication. This was particularly striking when both IRE1α and ATF6 branches of the UPR were inhibited, reducing SARS-CoV-2 virion release (~1,000-fold). Together, these data highlight the UPR as a promising antiviral target to combat coronavirus infection. |
| format | Article |
| id | doaj-art-eaf77300e108401e93e7f0b5b3c8dc13 |
| institution | OA Journals |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2021-06-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-eaf77300e108401e93e7f0b5b3c8dc132025-08-20T02:33:18ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742021-06-01176e100964410.1371/journal.ppat.1009644Manipulation of the unfolded protein response: A pharmacological strategy against coronavirus infection.Liliana Echavarría-ConsuegraGeorgia M CookIdoia BusnadiegoCharlotte LefèvreSarah KeepKatherine BrownNicole DoyleGiulia DowgierKrzysztof FranaszekNathan A MooreStuart G SiddellErica BickertonBenjamin G HaleAndrew E FirthIan BrierleyNerea IrigoyenCoronavirus infection induces the unfolded protein response (UPR), a cellular signalling pathway composed of three branches, triggered by unfolded proteins in the endoplasmic reticulum (ER) due to high ER load. We have used RNA sequencing and ribosome profiling to investigate holistically the transcriptional and translational response to cellular infection by murine hepatitis virus (MHV), often used as a model for the Betacoronavirus genus to which the recently emerged SARS-CoV-2 also belongs. We found the UPR to be amongst the most significantly up-regulated pathways in response to MHV infection. To confirm and extend these observations, we show experimentally the induction of all three branches of the UPR in both MHV- and SARS-CoV-2-infected cells. Over-expression of the SARS-CoV-2 ORF8 or S proteins alone is itself sufficient to induce the UPR. Remarkably, pharmacological inhibition of the UPR greatly reduced the replication of both MHV and SARS-CoV-2, revealing the importance of this pathway for successful coronavirus replication. This was particularly striking when both IRE1α and ATF6 branches of the UPR were inhibited, reducing SARS-CoV-2 virion release (~1,000-fold). Together, these data highlight the UPR as a promising antiviral target to combat coronavirus infection.https://doi.org/10.1371/journal.ppat.1009644 |
| spellingShingle | Liliana Echavarría-Consuegra Georgia M Cook Idoia Busnadiego Charlotte Lefèvre Sarah Keep Katherine Brown Nicole Doyle Giulia Dowgier Krzysztof Franaszek Nathan A Moore Stuart G Siddell Erica Bickerton Benjamin G Hale Andrew E Firth Ian Brierley Nerea Irigoyen Manipulation of the unfolded protein response: A pharmacological strategy against coronavirus infection. PLoS Pathogens |
| title | Manipulation of the unfolded protein response: A pharmacological strategy against coronavirus infection. |
| title_full | Manipulation of the unfolded protein response: A pharmacological strategy against coronavirus infection. |
| title_fullStr | Manipulation of the unfolded protein response: A pharmacological strategy against coronavirus infection. |
| title_full_unstemmed | Manipulation of the unfolded protein response: A pharmacological strategy against coronavirus infection. |
| title_short | Manipulation of the unfolded protein response: A pharmacological strategy against coronavirus infection. |
| title_sort | manipulation of the unfolded protein response a pharmacological strategy against coronavirus infection |
| url | https://doi.org/10.1371/journal.ppat.1009644 |
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