Middle East respiratory syndrome coronavirus ORF4b protein inhibits type I interferon production through both cytoplasmic and nuclear targets.
Identifieur interne : 001445 ( PubMed/Checkpoint ); précédent : 001444; suivant : 001446Middle East respiratory syndrome coronavirus ORF4b protein inhibits type I interferon production through both cytoplasmic and nuclear targets.
Auteurs : Yang Yang [République populaire de Chine] ; Fei Ye [République populaire de Chine] ; Na Zhu [République populaire de Chine] ; Wenling Wang [République populaire de Chine] ; Yao Deng [République populaire de Chine] ; Zhengdong Zhao [République populaire de Chine] ; Wenjie Tan [République populaire de Chine]Source :
- Scientific reports [ 2045-2322 ] ; 2015.
Descripteurs français
- KwdFr :
- Cellules HeLa (virologie), Coronavirus du syndrome respiratoire du Moyen-Orient (pathogénicité), Cytoplasme (métabolisme), Cytoplasme (virologie), Facteur-3 de régulation d'interféron (génétique), Facteur-3 de régulation d'interféron (métabolisme), Facteur-7 de régulation d'interféron (métabolisme), Humains, Hélicase IFIH1 inductrice de l'interféron (génétique), Hélicase IFIH1 inductrice de l'interféron (métabolisme), I-kappa B Kinase (métabolisme), Interactions hôte-pathogène, Interféron bêta (génétique), Interféron bêta (métabolisme), Noyau de la cellule (métabolisme), Noyau de la cellule (virologie), Phosphorylation, Protein-Serine-Threonine Kinases (métabolisme), Protéine-58 à domaine DEAD (génétique), Protéine-58 à domaine DEAD (métabolisme), Protéines adaptatrices de la transduction du signal (métabolisme), Protéines virales (génétique), Protéines virales (métabolisme), Protéines virales (pharmacologie).
- MESH :
- génétique : Facteur-3 de régulation d'interféron, Hélicase IFIH1 inductrice de l'interféron, Interféron bêta, Protéine-58 à domaine DEAD, Protéines virales.
- métabolisme : Cytoplasme, Facteur-3 de régulation d'interféron, Facteur-7 de régulation d'interféron, Hélicase IFIH1 inductrice de l'interféron, I-kappa B Kinase, Interféron bêta, Noyau de la cellule, Protein-Serine-Threonine Kinases, Protéine-58 à domaine DEAD, Protéines adaptatrices de la transduction du signal, Protéines virales.
- pathogénicité : Coronavirus du syndrome respiratoire du Moyen-Orient.
- pharmacologie : Protéines virales.
- virologie : Cellules HeLa, Cytoplasme, Noyau de la cellule.
- Humains, Interactions hôte-pathogène, Phosphorylation.
English descriptors
- KwdEn :
- Adaptor Proteins, Signal Transducing (metabolism), Cell Nucleus (metabolism), Cell Nucleus (virology), Cytoplasm (metabolism), Cytoplasm (virology), DEAD Box Protein 58 (genetics), DEAD Box Protein 58 (metabolism), HeLa Cells (virology), Host-Pathogen Interactions, Humans, I-kappa B Kinase (metabolism), Interferon Regulatory Factor-3 (genetics), Interferon Regulatory Factor-3 (metabolism), Interferon Regulatory Factor-7 (metabolism), Interferon-Induced Helicase, IFIH1 (genetics), Interferon-Induced Helicase, IFIH1 (metabolism), Interferon-beta (genetics), Interferon-beta (metabolism), Middle East Respiratory Syndrome Coronavirus (pathogenicity), Phosphorylation, Protein-Serine-Threonine Kinases (metabolism), Viral Proteins (genetics), Viral Proteins (metabolism), Viral Proteins (pharmacology).
- MESH :
- chemical , genetics : DEAD Box Protein 58, Interferon Regulatory Factor-3, Interferon-Induced Helicase, IFIH1, Interferon-beta, Viral Proteins.
- chemical , metabolism : Adaptor Proteins, Signal Transducing, DEAD Box Protein 58, I-kappa B Kinase, Interferon Regulatory Factor-3, Interferon Regulatory Factor-7, Interferon-Induced Helicase, IFIH1, Interferon-beta, Protein-Serine-Threonine Kinases, Viral Proteins.
- metabolism : Cell Nucleus, Cytoplasm.
- pathogenicity : Middle East Respiratory Syndrome Coronavirus.
- chemical , pharmacology : Viral Proteins.
- virology : Cell Nucleus, Cytoplasm, HeLa Cells.
- Host-Pathogen Interactions, Humans, Phosphorylation.
Abstract
Middle East respiratory syndrome coronavirus (MERS-CoV) is a novel and highly pathogenic human coronavirus and has quickly spread to other countries in the Middle East, Europe, North Africa and Asia since 2012. Previous studies have shown that MERS-CoV ORF4b antagonizes the early antiviral alpha/beta interferon (IFN-α/β) response, which may significantly contribute to MERS-CoV pathogenesis; however, the underlying mechanism is poorly understood. Here, we found that ORF4b in the cytoplasm could specifically bind to TANK binding kinase 1 (TBK1) and IκB kinase epsilon (IKKε), suppress the molecular interaction between mitochondrial antiviral signaling protein (MAVS) and IKKε, and inhibit IFN regulatory factor 3 (IRF3) phosphorylation and subsequent IFN-β production. Further analysis showed that ORF4b could also inhibit IRF3 and IRF7-induced production of IFN-β, whereas deletion of the nuclear localization signal of ORF4b abrogated its ability to inhibit IRF3 and IRF7-induced production of IFN-β, but not IFN-β production induced by RIG-I, MDA5, MAVS, IKKε, and TBK-1, suggesting that ORF4b could inhibit the induction of IFN-β in both the cytoplasm and nucleus. Collectively, these results indicate that MERS-CoV ORF4b inhibits the induction of type I IFN through a direct interaction with IKKε/TBK1 in the cytoplasm, and also in the nucleus with unknown mechanism. Viruses have evolved multiple strategies to evade or thwart a host's antiviral responses. A novel human coronavirus (HCoV), Middle East respiratory syndrome coronavirus (MERS-CoV), is distinguished from other coronaviruses by its high pathogenicity and mortality. However, virulence determinants that distinguish MERS-CoV from other HCoVs have yet to be identified. MERS-CoV ORF4b antagonizes the early antiviral response, which may contribute to MERS-CoV pathogenesis. Here, we report the identification of the interferon (IFN) antagonism mechanism of MERS-CoV ORF4b. MERS-CoV ORF4b inhibits the production of type I IFN through a direct interaction with IKKε/TBK1 in the cytoplasm, and also in the nucleus with unknown mechanism. These findings provide a rationale for the novel pathogenesis of MERS-CoV as well as a basis for developing a candidate therapeutic against this virus.
DOI: 10.1038/srep17554
PubMed: 26631542
Affiliations:
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pubmed:26631542Le document en format XML
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<term>Cytoplasm (metabolism)</term>
<term>Cytoplasm (virology)</term>
<term>DEAD Box Protein 58 (genetics)</term>
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<term>HeLa Cells (virology)</term>
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<front><div type="abstract" xml:lang="en">Middle East respiratory syndrome coronavirus (MERS-CoV) is a novel and highly pathogenic human coronavirus and has quickly spread to other countries in the Middle East, Europe, North Africa and Asia since 2012. Previous studies have shown that MERS-CoV ORF4b antagonizes the early antiviral alpha/beta interferon (IFN-α/β) response, which may significantly contribute to MERS-CoV pathogenesis; however, the underlying mechanism is poorly understood. Here, we found that ORF4b in the cytoplasm could specifically bind to TANK binding kinase 1 (TBK1) and IκB kinase epsilon (IKKε), suppress the molecular interaction between mitochondrial antiviral signaling protein (MAVS) and IKKε, and inhibit IFN regulatory factor 3 (IRF3) phosphorylation and subsequent IFN-β production. Further analysis showed that ORF4b could also inhibit IRF3 and IRF7-induced production of IFN-β, whereas deletion of the nuclear localization signal of ORF4b abrogated its ability to inhibit IRF3 and IRF7-induced production of IFN-β, but not IFN-β production induced by RIG-I, MDA5, MAVS, IKKε, and TBK-1, suggesting that ORF4b could inhibit the induction of IFN-β in both the cytoplasm and nucleus. Collectively, these results indicate that MERS-CoV ORF4b inhibits the induction of type I IFN through a direct interaction with IKKε/TBK1 in the cytoplasm, and also in the nucleus with unknown mechanism. Viruses have evolved multiple strategies to evade or thwart a host's antiviral responses. A novel human coronavirus (HCoV), Middle East respiratory syndrome coronavirus (MERS-CoV), is distinguished from other coronaviruses by its high pathogenicity and mortality. However, virulence determinants that distinguish MERS-CoV from other HCoVs have yet to be identified. MERS-CoV ORF4b antagonizes the early antiviral response, which may contribute to MERS-CoV pathogenesis. Here, we report the identification of the interferon (IFN) antagonism mechanism of MERS-CoV ORF4b. MERS-CoV ORF4b inhibits the production of type I IFN through a direct interaction with IKKε/TBK1 in the cytoplasm, and also in the nucleus with unknown mechanism. These findings provide a rationale for the novel pathogenesis of MERS-CoV as well as a basis for developing a candidate therapeutic against this virus. </div>
</front>
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<Abstract><AbstractText>Middle East respiratory syndrome coronavirus (MERS-CoV) is a novel and highly pathogenic human coronavirus and has quickly spread to other countries in the Middle East, Europe, North Africa and Asia since 2012. Previous studies have shown that MERS-CoV ORF4b antagonizes the early antiviral alpha/beta interferon (IFN-α/β) response, which may significantly contribute to MERS-CoV pathogenesis; however, the underlying mechanism is poorly understood. Here, we found that ORF4b in the cytoplasm could specifically bind to TANK binding kinase 1 (TBK1) and IκB kinase epsilon (IKKε), suppress the molecular interaction between mitochondrial antiviral signaling protein (MAVS) and IKKε, and inhibit IFN regulatory factor 3 (IRF3) phosphorylation and subsequent IFN-β production. Further analysis showed that ORF4b could also inhibit IRF3 and IRF7-induced production of IFN-β, whereas deletion of the nuclear localization signal of ORF4b abrogated its ability to inhibit IRF3 and IRF7-induced production of IFN-β, but not IFN-β production induced by RIG-I, MDA5, MAVS, IKKε, and TBK-1, suggesting that ORF4b could inhibit the induction of IFN-β in both the cytoplasm and nucleus. Collectively, these results indicate that MERS-CoV ORF4b inhibits the induction of type I IFN through a direct interaction with IKKε/TBK1 in the cytoplasm, and also in the nucleus with unknown mechanism. Viruses have evolved multiple strategies to evade or thwart a host's antiviral responses. A novel human coronavirus (HCoV), Middle East respiratory syndrome coronavirus (MERS-CoV), is distinguished from other coronaviruses by its high pathogenicity and mortality. However, virulence determinants that distinguish MERS-CoV from other HCoVs have yet to be identified. MERS-CoV ORF4b antagonizes the early antiviral response, which may contribute to MERS-CoV pathogenesis. Here, we report the identification of the interferon (IFN) antagonism mechanism of MERS-CoV ORF4b. MERS-CoV ORF4b inhibits the production of type I IFN through a direct interaction with IKKε/TBK1 in the cytoplasm, and also in the nucleus with unknown mechanism. These findings provide a rationale for the novel pathogenesis of MERS-CoV as well as a basis for developing a candidate therapeutic against this virus. </AbstractText>
</Abstract>
<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Yang</LastName>
<ForeName>Yang</ForeName>
<Initials>Y</Initials>
<AffiliationInfo><Affiliation>Key Laboratory of Medical Virology, Ministry of Health; National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, 102206, China.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Shenzhen Key Laboratory of Pathogen and Immunity, Shenzhen Third People's Hospital, Shenzhen, China.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Ye</LastName>
<ForeName>Fei</ForeName>
<Initials>F</Initials>
<AffiliationInfo><Affiliation>Key Laboratory of Medical Virology, Ministry of Health; National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, 102206, China.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Zhu</LastName>
<ForeName>Na</ForeName>
<Initials>N</Initials>
<AffiliationInfo><Affiliation>Key Laboratory of Medical Virology, Ministry of Health; National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, 102206, China.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Wang</LastName>
<ForeName>Wenling</ForeName>
<Initials>W</Initials>
<AffiliationInfo><Affiliation>Key Laboratory of Medical Virology, Ministry of Health; National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, 102206, China.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Deng</LastName>
<ForeName>Yao</ForeName>
<Initials>Y</Initials>
<AffiliationInfo><Affiliation>Key Laboratory of Medical Virology, Ministry of Health; National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, 102206, China.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Zhao</LastName>
<ForeName>Zhengdong</ForeName>
<Initials>Z</Initials>
<AffiliationInfo><Affiliation>Key Laboratory of Pathogen System Biology, Ministry of Health; Institute of Pathogen Biology, Chinese Academy of Medical Sciences, Beijing, 100176, China.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Tan</LastName>
<ForeName>Wenjie</ForeName>
<Initials>W</Initials>
<AffiliationInfo><Affiliation>Key Laboratory of Medical Virology, Ministry of Health; National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, 102206, China.</Affiliation>
</AffiliationInfo>
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<Language>eng</Language>
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<PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType>
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<ArticleDate DateType="Electronic"><Year>2015</Year>
<Month>12</Month>
<Day>03</Day>
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<MedlineTA>Sci Rep</MedlineTA>
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<ISSNLinking>2045-2322</ISSNLinking>
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<affiliations><list><country><li>République populaire de Chine</li>
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<name sortKey="Deng, Yao" sort="Deng, Yao" uniqKey="Deng Y" first="Yao" last="Deng">Yao Deng</name>
<name sortKey="Tan, Wenjie" sort="Tan, Wenjie" uniqKey="Tan W" first="Wenjie" last="Tan">Wenjie Tan</name>
<name sortKey="Wang, Wenling" sort="Wang, Wenling" uniqKey="Wang W" first="Wenling" last="Wang">Wenling Wang</name>
<name sortKey="Ye, Fei" sort="Ye, Fei" uniqKey="Ye F" first="Fei" last="Ye">Fei Ye</name>
<name sortKey="Zhao, Zhengdong" sort="Zhao, Zhengdong" uniqKey="Zhao Z" first="Zhengdong" last="Zhao">Zhengdong Zhao</name>
<name sortKey="Zhu, Na" sort="Zhu, Na" uniqKey="Zhu N" first="Na" last="Zhu">Na Zhu</name>
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