Middle East respiratory syndrome coronavirus ORF4b protein inhibits type I interferon production through both cytoplasmic and nuclear targets
Identifieur interne : 000D71 ( Pmc/Checkpoint ); précédent : 000D70; suivant : 000D72Middle 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.
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.
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DOI: 10.1038/srep17554
PubMed: 26631542
PubMed Central: 4668369
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xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Beijing</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="GRID">grid.198530.6</institution-id><institution-id institution-id-type="ISNI">0000 0000 8803 2373</institution-id><institution>National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention,</institution></institution-wrap>Beijing, 102206 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Beijing</wicri:regionArea></affiliation></author><author><name sortKey="Zhao, Zhengdong" sort="Zhao, Zhengdong" uniqKey="Zhao Z" first="Zhengdong" last="Zhao">Zhengdong Zhao</name><affiliation wicri:level="1"><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="GRID">grid.453135.5</institution-id><institution-id institution-id-type="ISNI">0000 0004 1769 3691</institution-id><institution>Key Laboratory of Pathogen System Biology, Ministry of Health,</institution></institution-wrap>Beijing, 100176 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Beijing</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="Aff5"><institution-wrap><institution-id institution-id-type="GRID">grid.410318.f</institution-id><institution-id institution-id-type="ISNI">0000 0004 0632 3409</institution-id><institution>Institute of Pathogen Biology, Chinese Academy of Medical Sciences,</institution></institution-wrap>Beijing, 100176 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Beijing</wicri:regionArea></affiliation></author><author><name sortKey="Tan, Wenjie" sort="Tan, Wenjie" uniqKey="Tan W" first="Wenjie" last="Tan">Wenjie Tan</name><affiliation wicri:level="1"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="GRID">grid.453135.5</institution-id><institution-id institution-id-type="ISNI">0000 0004 1769 3691</institution-id><institution>Key Laboratory of Medical Virology, Ministry of Health,</institution></institution-wrap>Beijing, 102206 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Beijing</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="GRID">grid.198530.6</institution-id><institution-id institution-id-type="ISNI">0000 0000 8803 2373</institution-id><institution>National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention,</institution></institution-wrap>Beijing, 102206 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Beijing</wicri:regionArea></affiliation></author></analytic><series><title level="j">Scientific Reports</title><idno type="eISSN">2045-2322</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>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.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Zaki, Am" uniqKey="Zaki A">AM Zaki</name></author><author><name sortKey="Van Boheemen, S" uniqKey="Van Boheemen S">S van Boheemen</name></author><author><name sortKey="Bestebroer, Tm" uniqKey="Bestebroer T">TM Bestebroer</name></author><author><name sortKey="Osterhaus, Ad" uniqKey="Osterhaus A">AD Osterhaus</name></author><author><name sortKey="Fouchier, Ra" uniqKey="Fouchier R">RA Fouchier</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Butler, D" uniqKey="Butler D">D Butler</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Breban, R" uniqKey="Breban R">R Breban</name></author><author><name sortKey="Riou, J" uniqKey="Riou J">J 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Sci Rep</journal-id><journal-id journal-id-type="iso-abbrev">Sci Rep</journal-id><journal-title-group><journal-title>Scientific Reports</journal-title></journal-title-group><issn pub-type="epub">2045-2322</issn><publisher><publisher-name>Nature Publishing Group UK</publisher-name><publisher-loc>London</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">26631542</article-id><article-id pub-id-type="pmc">4668369</article-id><article-id pub-id-type="publisher-id">BFsrep17554</article-id><article-id pub-id-type="doi">10.1038/srep17554</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Middle East respiratory syndrome coronavirus ORF4b protein inhibits type I interferon production through both cytoplasmic and nuclear targets</article-title></title-group><contrib-group><contrib contrib-type="author" equal-contrib="yes"><name><surname>Yang</surname><given-names>Yang</given-names></name><xref ref-type="aff" rid="Aff1">1</xref><xref ref-type="aff" rid="Aff4">4</xref><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Ye</surname><given-names>Fei</given-names></name><xref ref-type="aff" rid="Aff1">1</xref><xref ref-type="aff" rid="Aff4">4</xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Zhu</surname><given-names>Na</given-names></name><xref ref-type="aff" rid="Aff1">1</xref><xref ref-type="aff" rid="Aff4">4</xref></contrib><contrib contrib-type="author"><name><surname>Wang</surname><given-names>Wenling</given-names></name><xref ref-type="aff" rid="Aff1">1</xref><xref ref-type="aff" rid="Aff4">4</xref></contrib><contrib contrib-type="author"><name><surname>Deng</surname><given-names>Yao</given-names></name><xref ref-type="aff" rid="Aff1">1</xref><xref ref-type="aff" rid="Aff4">4</xref></contrib><contrib contrib-type="author"><name><surname>Zhao</surname><given-names>Zhengdong</given-names></name><xref ref-type="aff" rid="Aff3">3</xref><xref ref-type="aff" rid="Aff5">5</xref></contrib><contrib contrib-type="author"><name><surname>Tan</surname><given-names>Wenjie</given-names></name><address><email>tanwj28@163.com</email></address><xref ref-type="aff" rid="Aff1">1</xref><xref ref-type="aff" rid="Aff4">4</xref></contrib><aff id="Aff1"><label>1</label><institution-wrap><institution-id institution-id-type="GRID">grid.453135.5</institution-id><institution-id institution-id-type="ISNI">0000 0004 1769 3691</institution-id><institution>Key Laboratory of Medical Virology, Ministry of Health,</institution></institution-wrap>Beijing, 102206 China</aff><aff id="Aff4"><label>4</label><institution-wrap><institution-id institution-id-type="GRID">grid.198530.6</institution-id><institution-id institution-id-type="ISNI">0000 0000 8803 2373</institution-id><institution>National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention,</institution></institution-wrap>Beijing, 102206 China</aff><aff id="Aff2"><label>2</label><institution-wrap><institution-id institution-id-type="GRID">grid.410741.7</institution-id><institution>Shenzhen Key Laboratory of Pathogen and Immunity, Shenzhen Third People’s Hospital,</institution></institution-wrap>Shenzhen, China</aff><aff id="Aff3"><label>3</label><institution-wrap><institution-id institution-id-type="GRID">grid.453135.5</institution-id><institution-id institution-id-type="ISNI">0000 0004 1769 3691</institution-id><institution>Key Laboratory of Pathogen System Biology, Ministry of Health,</institution></institution-wrap>Beijing, 100176 China</aff><aff id="Aff5"><label>5</label><institution-wrap><institution-id institution-id-type="GRID">grid.410318.f</institution-id><institution-id institution-id-type="ISNI">0000 0004 0632 3409</institution-id><institution>Institute of Pathogen Biology, Chinese Academy of Medical Sciences,</institution></institution-wrap>Beijing, 100176 China</aff></contrib-group><pub-date pub-type="epub"><day>3</day><month>12</month><year>2015</year></pub-date><pub-date pub-type="pmc-release"><day>3</day><month>12</month><year>2015</year></pub-date><pub-date pub-type="collection"><year>2015</year></pub-date><volume>5</volume><elocation-id>17554</elocation-id><history><date date-type="received"><day>10</day><month>7</month><year>2015</year></date><date date-type="accepted"><day>2</day><month>11</month><year>2015</year></date></history><permissions><copyright-statement>© The Author(s) 2015</copyright-statement><license license-type="OpenAccess"><license-p>This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link></license-p></license></permissions><abstract id="Abs1"><p>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.</p></abstract><kwd-group kwd-group-type="npg-subject"><title>Subject terms</title><kwd>Viral infection</kwd><kwd>Infection</kwd></kwd-group><custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name><meta-value>© The Author(s) 2015</meta-value></custom-meta></custom-meta-group></article-meta></front></pmc><affiliations><list><country><li>République populaire de Chine</li></country></list><tree><country name="République populaire de Chine"><noRegion><name sortKey="Yang, Yang" sort="Yang, Yang" uniqKey="Yang Y" first="Yang" last="Yang">Yang Yang</name></noRegion><name sortKey="Deng, Yao" sort="Deng, Yao" uniqKey="Deng Y" first="Yao" last="Deng">Yao Deng</name><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="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="Wang, Wenling" sort="Wang, Wenling" uniqKey="Wang W" first="Wenling" last="Wang">Wenling Wang</name><name sortKey="Yang, Yang" sort="Yang, Yang" uniqKey="Yang Y" first="Yang" last="Yang">Yang Yang</name><name sortKey="Yang, Yang" sort="Yang, Yang" uniqKey="Yang Y" first="Yang" last="Yang">Yang Yang</name><name sortKey="Ye, Fei" sort="Ye, Fei" uniqKey="Ye F" first="Fei" last="Ye">Fei Ye</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="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><name sortKey="Zhu, Na" sort="Zhu, Na" uniqKey="Zhu N" first="Na" last="Zhu">Na Zhu</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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