The endoplasmic reticulum stress sensor IRE1α protects cells from apoptosis induced by the coronavirus infectious bronchitis virus
The unfolded-protein response (UPR) is a signal transduction cascade triggered by perturbation of the homeostasis of the endoplasmic reticulum (ER). UPR resolves ER stress by activating a cascade of cellular responses, including the induction of molecular chaperones, translational attenuation, ER-as...
| Main Authors: | , , |
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| Format: | Journal Article |
| Language: | English |
| Published: |
2015
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| Online Access: | https://hdl.handle.net/10356/79398 http://hdl.handle.net/10220/25719 |
| _version_ | 1826123444746452992 |
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| author | Liu, Ding Xiang Fung, To Sing Liao, Ying |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Liu, Ding Xiang Fung, To Sing Liao, Ying |
| author_sort | Liu, Ding Xiang |
| collection | NTU |
| description | The unfolded-protein response (UPR) is a signal transduction cascade triggered by perturbation of the homeostasis of the endoplasmic reticulum (ER). UPR resolves ER stress by activating a cascade of cellular responses, including the induction of molecular chaperones, translational attenuation, ER-associated degradation, and other mechanisms. Under prolonged and irremediable ER stress, however, the UPR can also trigger apoptosis. Here, we report that in cells infected with the avian coronavirus infectious bronchitis virus (IBV), ER stress was induced and the IRE1α-XBP1 pathway of UPR was activated. Knockdown and overexpression experiments demonstrated that IRE1α protects infected cells from IBV-induced apoptosis, which required both its kinase and RNase activities. Our data also suggest that splicing of XBP1 mRNA by IRE1α appears to convert XBP1 from a proapoptotic XBP1u protein to a prosurvival XBP1s protein. Moreover, IRE1α antagonized IBV-induced apoptosis by modulating the phosphorylation status of the proapoptotic c-Jun N-terminal kinase (JNK) and the prosurvival RAC–alpha serine/threonine-protein kinase (Akt). Taken together, the data indicate that the ER stress sensor IRE1α is activated in IBV-infected cells and serves as a survival factor during coronavirus infection. IMPORTANCE: Animal coronaviruses are important veterinary viruses, which could cross the species barrier, becoming severe human pathogens. Molecular characterization of the interactions between coronaviruses and host cells is pivotal to understanding the pathogenicity and species specificity of coronavirus infection. It has been well established that the endoplasmic reticulum (ER) is closely associated with coronavirus replication. Here, we report that inositol-requiring protein 1 alpha (IRE1α), a key sensor of ER stress, is activated in cells infected with the avian coronavirus infectious bronchitis virus (IBV). Moreover, IRE1α is shown to protect the infected cells from apoptosis by modulating the unfolded-protein response (UPR) and two kinases related to cell survival. This study demonstrates that UPR activation constitutes a major aspect of coronavirus-host interactions. Manipulations of the coronavirus-induced UPR may provide novel therapeutic targets for the control of coronavirus infection and pathogenesis. |
| first_indexed | 2024-10-01T06:04:46Z |
| format | Journal Article |
| id | ntu-10356/79398 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T06:04:46Z |
| publishDate | 2015 |
| record_format | dspace |
| spelling | ntu-10356/793982023-02-28T16:59:22Z The endoplasmic reticulum stress sensor IRE1α protects cells from apoptosis induced by the coronavirus infectious bronchitis virus Liu, Ding Xiang Fung, To Sing Liao, Ying School of Biological Sciences DRNTU::Science::Biological sciences::Microbiology::Bacteria The unfolded-protein response (UPR) is a signal transduction cascade triggered by perturbation of the homeostasis of the endoplasmic reticulum (ER). UPR resolves ER stress by activating a cascade of cellular responses, including the induction of molecular chaperones, translational attenuation, ER-associated degradation, and other mechanisms. Under prolonged and irremediable ER stress, however, the UPR can also trigger apoptosis. Here, we report that in cells infected with the avian coronavirus infectious bronchitis virus (IBV), ER stress was induced and the IRE1α-XBP1 pathway of UPR was activated. Knockdown and overexpression experiments demonstrated that IRE1α protects infected cells from IBV-induced apoptosis, which required both its kinase and RNase activities. Our data also suggest that splicing of XBP1 mRNA by IRE1α appears to convert XBP1 from a proapoptotic XBP1u protein to a prosurvival XBP1s protein. Moreover, IRE1α antagonized IBV-induced apoptosis by modulating the phosphorylation status of the proapoptotic c-Jun N-terminal kinase (JNK) and the prosurvival RAC–alpha serine/threonine-protein kinase (Akt). Taken together, the data indicate that the ER stress sensor IRE1α is activated in IBV-infected cells and serves as a survival factor during coronavirus infection. IMPORTANCE: Animal coronaviruses are important veterinary viruses, which could cross the species barrier, becoming severe human pathogens. Molecular characterization of the interactions between coronaviruses and host cells is pivotal to understanding the pathogenicity and species specificity of coronavirus infection. It has been well established that the endoplasmic reticulum (ER) is closely associated with coronavirus replication. Here, we report that inositol-requiring protein 1 alpha (IRE1α), a key sensor of ER stress, is activated in cells infected with the avian coronavirus infectious bronchitis virus (IBV). Moreover, IRE1α is shown to protect the infected cells from apoptosis by modulating the unfolded-protein response (UPR) and two kinases related to cell survival. This study demonstrates that UPR activation constitutes a major aspect of coronavirus-host interactions. Manipulations of the coronavirus-induced UPR may provide novel therapeutic targets for the control of coronavirus infection and pathogenesis. Published version 2015-06-02T02:37:49Z 2019-12-06T13:24:24Z 2015-06-02T02:37:49Z 2019-12-06T13:24:24Z 2014 2014 Journal Article Fung, T. S., Liao, Y., & Liu, D. X. (2014). The endoplasmic reticulum stress sensor IRE1α protects cells from apoptosis induced by the coronavirus infectious bronchitis virus. Journal of virology, 88(21), 12752-12764. https://hdl.handle.net/10356/79398 http://hdl.handle.net/10220/25719 10.1128/JVI.02138-14 25142592 en Journal of virology © 2014 American Society for Microbiology. This paper was published in Journal of Virology and is made available as an electronic reprint (preprint) with permission of American Society for Microbiology. The paper can be found at the following official DOI: [http://dx.doi.org/10.1128/JVI.02138-14]. One print or electronic copy may be made for personal use only. Systematic or multiple reproduction, distribution to multiple locations via electronic or other means, duplication of any material in this paper for a fee or for commercial purposes, or modification of the content of the paper is prohibited and is subject to penalties under law. 13 p. application/pdf |
| spellingShingle | DRNTU::Science::Biological sciences::Microbiology::Bacteria Liu, Ding Xiang Fung, To Sing Liao, Ying The endoplasmic reticulum stress sensor IRE1α protects cells from apoptosis induced by the coronavirus infectious bronchitis virus |
| title | The endoplasmic reticulum stress sensor IRE1α protects cells from apoptosis induced by the coronavirus infectious bronchitis virus |
| title_full | The endoplasmic reticulum stress sensor IRE1α protects cells from apoptosis induced by the coronavirus infectious bronchitis virus |
| title_fullStr | The endoplasmic reticulum stress sensor IRE1α protects cells from apoptosis induced by the coronavirus infectious bronchitis virus |
| title_full_unstemmed | The endoplasmic reticulum stress sensor IRE1α protects cells from apoptosis induced by the coronavirus infectious bronchitis virus |
| title_short | The endoplasmic reticulum stress sensor IRE1α protects cells from apoptosis induced by the coronavirus infectious bronchitis virus |
| title_sort | endoplasmic reticulum stress sensor ire1α protects cells from apoptosis induced by the coronavirus infectious bronchitis virus |
| topic | DRNTU::Science::Biological sciences::Microbiology::Bacteria |
| url | https://hdl.handle.net/10356/79398 http://hdl.handle.net/10220/25719 |
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