The unfolded protein response components IRE1α and XBP1 promote human coronavirus infection
ABSTRACT The cellular processes that support human coronavirus replication and contribute to the pathogenesis of severe disease remain incompletely understood. Many viruses, including coronaviruses, cause endoplasmic reticulum (ER) stress during infection. IRE1α is a component of the cellular respon...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2023-08-01
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| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mbio.00540-23 |
| _version_ | 1797730254084636672 |
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| author | Jessica M. Oda Andreas B. den Hartigh Shoen M. Jackson Ana R. Tronco Susan L. Fink |
| author_facet | Jessica M. Oda Andreas B. den Hartigh Shoen M. Jackson Ana R. Tronco Susan L. Fink |
| author_sort | Jessica M. Oda |
| collection | DOAJ |
| description | ABSTRACT The cellular processes that support human coronavirus replication and contribute to the pathogenesis of severe disease remain incompletely understood. Many viruses, including coronaviruses, cause endoplasmic reticulum (ER) stress during infection. IRE1α is a component of the cellular response to ER stress that initiates non-conventional splicing of XBP1 mRNA. Spliced XBP1 encodes a transcription factor that induces the expression of ER-related targets. Activation of the IRE1α–XBP1 pathway occurs in association with risk factors for severe human coronavirus infection. In this study, we found that the human coronaviruses HCoV-OC43 (human coronavirus OC43) and SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) both robustly activate the IRE1α–XBP1 branch of the unfolded protein response in cultured cells. Using IRE1α nuclease inhibitors and genetic knockdown of IRE1α and XBP1, we found that these host factors are required for optimal replication of both viruses. Our data suggest that IRE1α supports infection downstream of initial viral attachment and entry. In addition, we found that ER stress–inducing conditions are sufficient to enhance human coronavirus replication. Furthermore, we found markedly increased XBP1 in circulation in human patients with severe coronavirus disease 2019 (COVID-19). Together, these results demonstrate the importance of IRE1α and XBP1 for human coronavirus infection. IMPORTANCE There is a critical need to understand the cellular processes co-opted during human coronavirus replication, with an emphasis on identifying mechanisms underlying severe disease and potential therapeutic targets. Here, we demonstrate that the host proteins IRE1α and XBP1 are required for robust infection by the human coronaviruses, SARS-CoV-2 and HCoV-OC43. IRE1α and XBP1 participate in the cellular response to ER stress and are activated during conditions that predispose to severe COVID-19. We found enhanced viral replication with exogenous IRE1α activation, and evidence that this pathway is activated in humans during severe COVID-19. Together, these results demonstrate the importance of IRE1α and XBP1 for human coronavirus infection. |
| first_indexed | 2024-03-12T11:41:35Z |
| format | Article |
| id | doaj.art-6221dbebe2f54cff9cd51cd20f86b166 |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-03-12T11:41:35Z |
| publishDate | 2023-08-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-6221dbebe2f54cff9cd51cd20f86b1662023-08-31T15:04:20ZengAmerican Society for MicrobiologymBio2150-75112023-08-0114410.1128/mbio.00540-23The unfolded protein response components IRE1α and XBP1 promote human coronavirus infectionJessica M. Oda0Andreas B. den Hartigh1Shoen M. Jackson2Ana R. Tronco3Susan L. Fink4Department of Laboratory Medicine and Pathology, University of Washington , Seattle, Washington, USADepartment of Laboratory Medicine and Pathology, University of Washington , Seattle, Washington, USADepartment of Laboratory Medicine and Pathology, University of Washington , Seattle, Washington, USADepartment of Laboratory Medicine and Pathology, University of Washington , Seattle, Washington, USADepartment of Laboratory Medicine and Pathology, University of Washington , Seattle, Washington, USAABSTRACT The cellular processes that support human coronavirus replication and contribute to the pathogenesis of severe disease remain incompletely understood. Many viruses, including coronaviruses, cause endoplasmic reticulum (ER) stress during infection. IRE1α is a component of the cellular response to ER stress that initiates non-conventional splicing of XBP1 mRNA. Spliced XBP1 encodes a transcription factor that induces the expression of ER-related targets. Activation of the IRE1α–XBP1 pathway occurs in association with risk factors for severe human coronavirus infection. In this study, we found that the human coronaviruses HCoV-OC43 (human coronavirus OC43) and SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) both robustly activate the IRE1α–XBP1 branch of the unfolded protein response in cultured cells. Using IRE1α nuclease inhibitors and genetic knockdown of IRE1α and XBP1, we found that these host factors are required for optimal replication of both viruses. Our data suggest that IRE1α supports infection downstream of initial viral attachment and entry. In addition, we found that ER stress–inducing conditions are sufficient to enhance human coronavirus replication. Furthermore, we found markedly increased XBP1 in circulation in human patients with severe coronavirus disease 2019 (COVID-19). Together, these results demonstrate the importance of IRE1α and XBP1 for human coronavirus infection. IMPORTANCE There is a critical need to understand the cellular processes co-opted during human coronavirus replication, with an emphasis on identifying mechanisms underlying severe disease and potential therapeutic targets. Here, we demonstrate that the host proteins IRE1α and XBP1 are required for robust infection by the human coronaviruses, SARS-CoV-2 and HCoV-OC43. IRE1α and XBP1 participate in the cellular response to ER stress and are activated during conditions that predispose to severe COVID-19. We found enhanced viral replication with exogenous IRE1α activation, and evidence that this pathway is activated in humans during severe COVID-19. Together, these results demonstrate the importance of IRE1α and XBP1 for human coronavirus infection.https://journals.asm.org/doi/10.1128/mbio.00540-23coronavirusunfolded protein responseER stressSARS-CoV-2HCoV-OC43endoplasmic reticulum |
| spellingShingle | Jessica M. Oda Andreas B. den Hartigh Shoen M. Jackson Ana R. Tronco Susan L. Fink The unfolded protein response components IRE1α and XBP1 promote human coronavirus infection mBio coronavirus unfolded protein response ER stress SARS-CoV-2 HCoV-OC43 endoplasmic reticulum |
| title | The unfolded protein response components IRE1α and XBP1 promote human coronavirus infection |
| title_full | The unfolded protein response components IRE1α and XBP1 promote human coronavirus infection |
| title_fullStr | The unfolded protein response components IRE1α and XBP1 promote human coronavirus infection |
| title_full_unstemmed | The unfolded protein response components IRE1α and XBP1 promote human coronavirus infection |
| title_short | The unfolded protein response components IRE1α and XBP1 promote human coronavirus infection |
| title_sort | unfolded protein response components ire1α and xbp1 promote human coronavirus infection |
| topic | coronavirus unfolded protein response ER stress SARS-CoV-2 HCoV-OC43 endoplasmic reticulum |
| url | https://journals.asm.org/doi/10.1128/mbio.00540-23 |
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