Severe Acute Respiratory Syndrome Coronavirus 2 ORF8 Protein Inhibits Type I Interferon Production by Targeting HSP90B1 Signaling
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global pandemic that has currently infected over 430 million individuals worldwide. With the variant strains of SARS-CoV-2 emerging, a region of high mutation rates in ORF8 was identifie...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-05-01
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| Series: | Frontiers in Cellular and Infection Microbiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcimb.2022.899546/full |
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| author | Jiayi Chen Zixin Lu Xiuwen Yang Yezhen Zhou Jing Gao Shihao Zhang Shan Huang Jintai Cai Jianhai Yu Wei Zhao Bao Zhang |
| author_facet | Jiayi Chen Zixin Lu Xiuwen Yang Yezhen Zhou Jing Gao Shihao Zhang Shan Huang Jintai Cai Jianhai Yu Wei Zhao Bao Zhang |
| author_sort | Jiayi Chen |
| collection | DOAJ |
| description | Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global pandemic that has currently infected over 430 million individuals worldwide. With the variant strains of SARS-CoV-2 emerging, a region of high mutation rates in ORF8 was identified during the early pandemic, which resulted in a mutation from leucine (L) to serine (S) at amino acid 84. A typical feature of ORF8 is the immune evasion by suppressing interferon response; however, the mechanisms by which the two variants of ORF8 antagonize the type I interferon (IFN-I) pathway have not yet been clearly investigated. Here, we reported that SARS-CoV-2 ORF8L and ORF8S with no difference inhibit the production of IFN-β, MDA5, RIG-I, ISG15, ISG56, IRF3, and other IFN-related genes induced by poly(I:C). In addition, both ORF8L and ORF8S proteins were found to suppress the nuclear translocation of IRF3. Mechanistically, the SARS-CoV-2 ORF8 protein interacts with HSP90B1, which was later investigated to induce the production of IFN-β and IRF3. Taken together, these results indicate that SARS-CoV-2 ORF8 antagonizes the RIG-I/MDA-5 signaling pathway by targeting HSP90B1, which subsequently exhibits an inhibitory effect on the production of IFN-I. These functions appeared not to be influenced by the genotypes of ORF8L and ORF8S. Our study provides an explanation for the antiviral immune suppression of SARS-CoV-2 and suggests implications for the pathogenic mechanism and treatment of COVID-19. |
| first_indexed | 2024-12-12T13:21:08Z |
| format | Article |
| id | doaj.art-926b8b7d6ef74acbbb8ce0a945e28d87 |
| institution | Directory Open Access Journal |
| issn | 2235-2988 |
| language | English |
| last_indexed | 2024-12-12T13:21:08Z |
| publishDate | 2022-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular and Infection Microbiology |
| spelling | doaj.art-926b8b7d6ef74acbbb8ce0a945e28d872022-12-22T00:23:18ZengFrontiers Media S.A.Frontiers in Cellular and Infection Microbiology2235-29882022-05-011210.3389/fcimb.2022.899546899546Severe Acute Respiratory Syndrome Coronavirus 2 ORF8 Protein Inhibits Type I Interferon Production by Targeting HSP90B1 SignalingJiayi Chen0Zixin Lu1Xiuwen Yang2Yezhen Zhou3Jing Gao4Shihao Zhang5Shan Huang6Jintai Cai7Jianhai Yu8Wei Zhao9Bao Zhang10BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, ChinaBSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, ChinaBSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, ChinaBSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, ChinaBSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, ChinaBSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, ChinaDepartment of Epidemiology, School of Public Health, Southern Medical University, Guangzhou, ChinaBSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, ChinaBSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, ChinaBSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, ChinaBSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, ChinaCoronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global pandemic that has currently infected over 430 million individuals worldwide. With the variant strains of SARS-CoV-2 emerging, a region of high mutation rates in ORF8 was identified during the early pandemic, which resulted in a mutation from leucine (L) to serine (S) at amino acid 84. A typical feature of ORF8 is the immune evasion by suppressing interferon response; however, the mechanisms by which the two variants of ORF8 antagonize the type I interferon (IFN-I) pathway have not yet been clearly investigated. Here, we reported that SARS-CoV-2 ORF8L and ORF8S with no difference inhibit the production of IFN-β, MDA5, RIG-I, ISG15, ISG56, IRF3, and other IFN-related genes induced by poly(I:C). In addition, both ORF8L and ORF8S proteins were found to suppress the nuclear translocation of IRF3. Mechanistically, the SARS-CoV-2 ORF8 protein interacts with HSP90B1, which was later investigated to induce the production of IFN-β and IRF3. Taken together, these results indicate that SARS-CoV-2 ORF8 antagonizes the RIG-I/MDA-5 signaling pathway by targeting HSP90B1, which subsequently exhibits an inhibitory effect on the production of IFN-I. These functions appeared not to be influenced by the genotypes of ORF8L and ORF8S. Our study provides an explanation for the antiviral immune suppression of SARS-CoV-2 and suggests implications for the pathogenic mechanism and treatment of COVID-19.https://www.frontiersin.org/articles/10.3389/fcimb.2022.899546/fullSARS-CoV-2ORF8 proteintype I interferonHSP90B1IRF3 |
| spellingShingle | Jiayi Chen Zixin Lu Xiuwen Yang Yezhen Zhou Jing Gao Shihao Zhang Shan Huang Jintai Cai Jianhai Yu Wei Zhao Bao Zhang Severe Acute Respiratory Syndrome Coronavirus 2 ORF8 Protein Inhibits Type I Interferon Production by Targeting HSP90B1 Signaling Frontiers in Cellular and Infection Microbiology SARS-CoV-2 ORF8 protein type I interferon HSP90B1 IRF3 |
| title | Severe Acute Respiratory Syndrome Coronavirus 2 ORF8 Protein Inhibits Type I Interferon Production by Targeting HSP90B1 Signaling |
| title_full | Severe Acute Respiratory Syndrome Coronavirus 2 ORF8 Protein Inhibits Type I Interferon Production by Targeting HSP90B1 Signaling |
| title_fullStr | Severe Acute Respiratory Syndrome Coronavirus 2 ORF8 Protein Inhibits Type I Interferon Production by Targeting HSP90B1 Signaling |
| title_full_unstemmed | Severe Acute Respiratory Syndrome Coronavirus 2 ORF8 Protein Inhibits Type I Interferon Production by Targeting HSP90B1 Signaling |
| title_short | Severe Acute Respiratory Syndrome Coronavirus 2 ORF8 Protein Inhibits Type I Interferon Production by Targeting HSP90B1 Signaling |
| title_sort | severe acute respiratory syndrome coronavirus 2 orf8 protein inhibits type i interferon production by targeting hsp90b1 signaling |
| topic | SARS-CoV-2 ORF8 protein type I interferon HSP90B1 IRF3 |
| url | https://www.frontiersin.org/articles/10.3389/fcimb.2022.899546/full |
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