NS5 Conservative Site Is Required for Zika Virus to Restrict the RIG-I Signaling
During host–virus co-evolution, cells develop innate immune systems to inhibit virus invasion, while viruses employ strategies to suppress immune responses and maintain infection. Here, we reveal that Zika virus (ZIKV), a re-emerging arbovirus causing public concerns and devastating complications, r...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-02-01
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| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2020.00051/full |
| _version_ | 1819116218596982784 |
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| author | Aixin Li Wenbiao Wang Yingchong Wang Keli Chen Feng Xiao Dingwen Hu Lixia Hui Weiyong Liu Yuqian Feng Geng Li Qiuping Tan Yingle Liu Kailang Wu Jianguo Wu Jianguo Wu |
| author_facet | Aixin Li Wenbiao Wang Yingchong Wang Keli Chen Feng Xiao Dingwen Hu Lixia Hui Weiyong Liu Yuqian Feng Geng Li Qiuping Tan Yingle Liu Kailang Wu Jianguo Wu Jianguo Wu |
| author_sort | Aixin Li |
| collection | DOAJ |
| description | During host–virus co-evolution, cells develop innate immune systems to inhibit virus invasion, while viruses employ strategies to suppress immune responses and maintain infection. Here, we reveal that Zika virus (ZIKV), a re-emerging arbovirus causing public concerns and devastating complications, restricts host immune responses through a distinct mechanism. ZIKV nonstructural protein 5 (NS5) interacts with the host retinoic acid-inducible gene I (RIG-I), an essential signaling molecule for defending pathogen infections. NS5 subsequently represses K63-linked polyubiquitination of RIG-I, attenuates the phosphorylation and nuclear translocation of interferon regulatory factor 3 (IRF3), and inhibits the expression and production of interferon-β (IFN-β), thereby restricting the RIG-I signaling pathway. Interestingly, we demonstrate that the methyltransferase (MTase) domain of NS5 is required for the repression of RIG-I ubiquitination, IRF3 activation, and IFN-β production. Detailed studies further reveal that the conservative active site D146 of NS5 is critical for the suppression of the RIG-I signaling. Therefore, we uncover an essential role of NS5 conservative site D146 in ZIKV-mediated repression of innate immune system, illustrate a distinct mechanism by which ZIKV evades host immune responses, and discover a potential target for anti-viral infection. |
| first_indexed | 2024-12-22T05:13:36Z |
| format | Article |
| id | doaj.art-435f3afd33a34c1f8d875843927fbee6 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-22T05:13:36Z |
| publishDate | 2020-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-435f3afd33a34c1f8d875843927fbee62022-12-21T18:37:55ZengFrontiers Media S.A.Frontiers in Immunology1664-32242020-02-011110.3389/fimmu.2020.00051499522NS5 Conservative Site Is Required for Zika Virus to Restrict the RIG-I SignalingAixin Li0Wenbiao Wang1Yingchong Wang2Keli Chen3Feng Xiao4Dingwen Hu5Lixia Hui6Weiyong Liu7Yuqian Feng8Geng Li9Qiuping Tan10Yingle Liu11Kailang Wu12Jianguo Wu13Jianguo Wu14State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, ChinaGuangzhou Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, Guangzhou, ChinaState Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, ChinaState Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, ChinaState Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, ChinaState Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, ChinaState Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, ChinaState Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, ChinaGuangzhou Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, Guangzhou, ChinaGuangzhou Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, Guangzhou, ChinaGuangdong LongFan Biological Science and Technology Company, Foshan, ChinaGuangzhou Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, Guangzhou, ChinaState Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, ChinaState Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, ChinaGuangzhou Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, Guangzhou, ChinaDuring host–virus co-evolution, cells develop innate immune systems to inhibit virus invasion, while viruses employ strategies to suppress immune responses and maintain infection. Here, we reveal that Zika virus (ZIKV), a re-emerging arbovirus causing public concerns and devastating complications, restricts host immune responses through a distinct mechanism. ZIKV nonstructural protein 5 (NS5) interacts with the host retinoic acid-inducible gene I (RIG-I), an essential signaling molecule for defending pathogen infections. NS5 subsequently represses K63-linked polyubiquitination of RIG-I, attenuates the phosphorylation and nuclear translocation of interferon regulatory factor 3 (IRF3), and inhibits the expression and production of interferon-β (IFN-β), thereby restricting the RIG-I signaling pathway. Interestingly, we demonstrate that the methyltransferase (MTase) domain of NS5 is required for the repression of RIG-I ubiquitination, IRF3 activation, and IFN-β production. Detailed studies further reveal that the conservative active site D146 of NS5 is critical for the suppression of the RIG-I signaling. Therefore, we uncover an essential role of NS5 conservative site D146 in ZIKV-mediated repression of innate immune system, illustrate a distinct mechanism by which ZIKV evades host immune responses, and discover a potential target for anti-viral infection.https://www.frontiersin.org/article/10.3389/fimmu.2020.00051/fullIRF3IFN-βmethyltransferaseNS5RIG-Iubiquitination |
| spellingShingle | Aixin Li Wenbiao Wang Yingchong Wang Keli Chen Feng Xiao Dingwen Hu Lixia Hui Weiyong Liu Yuqian Feng Geng Li Qiuping Tan Yingle Liu Kailang Wu Jianguo Wu Jianguo Wu NS5 Conservative Site Is Required for Zika Virus to Restrict the RIG-I Signaling Frontiers in Immunology IRF3 IFN-β methyltransferase NS5 RIG-I ubiquitination |
| title | NS5 Conservative Site Is Required for Zika Virus to Restrict the RIG-I Signaling |
| title_full | NS5 Conservative Site Is Required for Zika Virus to Restrict the RIG-I Signaling |
| title_fullStr | NS5 Conservative Site Is Required for Zika Virus to Restrict the RIG-I Signaling |
| title_full_unstemmed | NS5 Conservative Site Is Required for Zika Virus to Restrict the RIG-I Signaling |
| title_short | NS5 Conservative Site Is Required for Zika Virus to Restrict the RIG-I Signaling |
| title_sort | ns5 conservative site is required for zika virus to restrict the rig i signaling |
| topic | IRF3 IFN-β methyltransferase NS5 RIG-I ubiquitination |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2020.00051/full |
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