SARS-CoV-2 ORF8 reshapes the ER through forming mixed disulfides with ER oxidoreductases
The replication machinery of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is closely associated with the endoplasmic reticulum (ER) in host cells. Activation of the unfolded protein response (UPR) is a strategy hijacked by coronavirus to facilitate its replication and suppress ho...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-08-01
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| Series: | Redox Biology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231722001604 |
| _version_ | 1828463022602977280 |
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| author | Ping Liu Xi Wang Yiwei Sun Hongyu Zhao Fang Cheng Jifeng Wang Fuquan Yang Junjie Hu Hong Zhang Chih-chen Wang Lei Wang |
| author_facet | Ping Liu Xi Wang Yiwei Sun Hongyu Zhao Fang Cheng Jifeng Wang Fuquan Yang Junjie Hu Hong Zhang Chih-chen Wang Lei Wang |
| author_sort | Ping Liu |
| collection | DOAJ |
| description | The replication machinery of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is closely associated with the endoplasmic reticulum (ER) in host cells. Activation of the unfolded protein response (UPR) is a strategy hijacked by coronavirus to facilitate its replication and suppress host innate immunity. Here, we have found that SARS-CoV-2 ORF8 protein accumulates in the ER and escapes the degradation system by forming mixed disulfide complexes with ER oxidoreductases. ORF8 induces the activation of three UPR pathways through targeting key UPR components, remodels ER morphology and accelerates protein trafficking. Moreover, small molecule reducing agents release ORF8 from the mixed disulfide complexes and facilitate its degradation, therefore mitigate ER stress. Our study reveals a unique mechanism by which SARS-CoV-2 ORF8 escapes degradation by host cells and regulates ER reshaping. Targeting ORF8-involved mixed disulfide complexes could be a new strategy to alleviate SARS-CoV-2 induced ER stress and related diseases. |
| first_indexed | 2024-12-11T02:47:36Z |
| format | Article |
| id | doaj.art-a7b3f20f43aa4354b2c610dd021420e5 |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-12-11T02:47:36Z |
| publishDate | 2022-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-a7b3f20f43aa4354b2c610dd021420e52022-12-22T01:23:24ZengElsevierRedox Biology2213-23172022-08-0154102388SARS-CoV-2 ORF8 reshapes the ER through forming mixed disulfides with ER oxidoreductasesPing Liu0Xi Wang1Yiwei Sun2Hongyu Zhao3Fang Cheng4Jifeng Wang5Fuquan Yang6Junjie Hu7Hong Zhang8Chih-chen Wang9Lei Wang10National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, ChinaNational Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China; Corresponding author.National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, ChinaNational Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, ChinaNational Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, ChinaLaboratory of Proteomics, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, ChinaLaboratory of Proteomics, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, ChinaNational Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, ChinaNational Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, ChinaNational Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, ChinaNational Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China; Corresponding author. National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.The replication machinery of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is closely associated with the endoplasmic reticulum (ER) in host cells. Activation of the unfolded protein response (UPR) is a strategy hijacked by coronavirus to facilitate its replication and suppress host innate immunity. Here, we have found that SARS-CoV-2 ORF8 protein accumulates in the ER and escapes the degradation system by forming mixed disulfide complexes with ER oxidoreductases. ORF8 induces the activation of three UPR pathways through targeting key UPR components, remodels ER morphology and accelerates protein trafficking. Moreover, small molecule reducing agents release ORF8 from the mixed disulfide complexes and facilitate its degradation, therefore mitigate ER stress. Our study reveals a unique mechanism by which SARS-CoV-2 ORF8 escapes degradation by host cells and regulates ER reshaping. Targeting ORF8-involved mixed disulfide complexes could be a new strategy to alleviate SARS-CoV-2 induced ER stress and related diseases.http://www.sciencedirect.com/science/article/pii/S2213231722001604Endoplasmic reticulumORF8RedoxSARS-CoV-2Unfolded protein response |
| spellingShingle | Ping Liu Xi Wang Yiwei Sun Hongyu Zhao Fang Cheng Jifeng Wang Fuquan Yang Junjie Hu Hong Zhang Chih-chen Wang Lei Wang SARS-CoV-2 ORF8 reshapes the ER through forming mixed disulfides with ER oxidoreductases Redox Biology Endoplasmic reticulum ORF8 Redox SARS-CoV-2 Unfolded protein response |
| title | SARS-CoV-2 ORF8 reshapes the ER through forming mixed disulfides with ER oxidoreductases |
| title_full | SARS-CoV-2 ORF8 reshapes the ER through forming mixed disulfides with ER oxidoreductases |
| title_fullStr | SARS-CoV-2 ORF8 reshapes the ER through forming mixed disulfides with ER oxidoreductases |
| title_full_unstemmed | SARS-CoV-2 ORF8 reshapes the ER through forming mixed disulfides with ER oxidoreductases |
| title_short | SARS-CoV-2 ORF8 reshapes the ER through forming mixed disulfides with ER oxidoreductases |
| title_sort | sars cov 2 orf8 reshapes the er through forming mixed disulfides with er oxidoreductases |
| topic | Endoplasmic reticulum ORF8 Redox SARS-CoV-2 Unfolded protein response |
| url | http://www.sciencedirect.com/science/article/pii/S2213231722001604 |
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