Middle East Respiratory Coronavirus Accessory Protein 4a Inhibits PKR-Mediated Antiviral Stress Responses
Identifieur interne : 000A89 ( Pmc/Checkpoint ); précédent : 000A88; suivant : 000A90Middle East Respiratory Coronavirus Accessory Protein 4a Inhibits PKR-Mediated Antiviral Stress Responses
Auteurs : Huib H. Rabouw [Pays-Bas] ; Martijn A. Langereis [Pays-Bas] ; Robert C. M. Knaap [Pays-Bas] ; Tim J. Dalebout [Pays-Bas] ; Javier Canton [Espagne] ; Isabel Sola [Espagne] ; Luis Enjuanes [Espagne] ; Peter J. Bredenbeek [Pays-Bas] ; Marjolein Kikkert [Pays-Bas] ; Raoul J. De Groot [Pays-Bas] ; Frank J. M. Van Kuppeveld [Pays-Bas]Source :
- PLoS Pathogens [ 1553-7366 ] ; 2016.
Abstract
Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe respiratory infections that can be life-threatening. To establish an infection and spread, MERS-CoV, like most other viruses, must navigate through an intricate network of antiviral host responses. Besides the well-known type I interferon (IFN-α/β) response, the protein kinase R (PKR)-mediated stress response is being recognized as an important innate response pathway. Upon detecting viral dsRNA, PKR phosphorylates eIF2α, leading to the inhibition of cellular and viral translation and the formation of stress granules (SGs), which are increasingly recognized as platforms for antiviral signaling pathways. It is unknown whether cellular infection by MERS-CoV activates the stress response pathway or whether the virus has evolved strategies to suppress this infection-limiting pathway. Here, we show that cellular infection with MERS-CoV does not lead to the formation of SGs. By transiently expressing the MERS-CoV accessory proteins individually, we identified a role of protein 4a (p4a) in preventing activation of the stress response pathway. Expression of MERS-CoV p4a impeded dsRNA-mediated PKR activation, thereby rescuing translation inhibition and preventing SG formation. In contrast, p4a failed to suppress stress response pathway activation that is independent of PKR and dsRNA. MERS-CoV p4a is a dsRNA binding protein. Mutation of the dsRNA binding motif in p4a disrupted its PKR antagonistic activity. By inserting p4a in a picornavirus lacking its natural PKR antagonist, we showed that p4a exerts PKR antagonistic activity also under infection conditions. However, a recombinant MERS-CoV deficient in p4a expression still suppressed SG formation, indicating the expression of at least one other stress response antagonist. This virus also suppressed the dsRNA-independent stress response pathway. Thus, MERS-CoV interferes with antiviral stress responses using at least two different mechanisms, with p4a suppressing the PKR-dependent stress response pathway, probably by sequestering dsRNA. MERS-CoV p4a represents the first coronavirus stress response antagonist described.
Url:
DOI: 10.1371/journal.ppat.1005982
PubMed: 27783669
PubMed Central: 5081173
Affiliations:
- Espagne, Pays-Bas
- Communauté de Madrid, Hollande-Méridionale, Utrecht (province)
- Leyde, Madrid, Utrecht
- Université d'Utrecht
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<front><div type="abstract" xml:lang="en"><p>Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe respiratory infections that can be life-threatening. To establish an infection and spread, MERS-CoV, like most other viruses, must navigate through an intricate network of antiviral host responses. Besides the well-known type I interferon (IFN-α/β) response, the protein kinase R (PKR)-mediated stress response is being recognized as an important innate response pathway. Upon detecting viral dsRNA, PKR phosphorylates eIF2α, leading to the inhibition of cellular and viral translation and the formation of stress granules (SGs), which are increasingly recognized as platforms for antiviral signaling pathways. It is unknown whether cellular infection by MERS-CoV activates the stress response pathway or whether the virus has evolved strategies to suppress this infection-limiting pathway. Here, we show that cellular infection with MERS-CoV does not lead to the formation of SGs. By transiently expressing the MERS-CoV accessory proteins individually, we identified a role of protein 4a (p4a) in preventing activation of the stress response pathway. Expression of MERS-CoV p4a impeded dsRNA-mediated PKR activation, thereby rescuing translation inhibition and preventing SG formation. In contrast, p4a failed to suppress stress response pathway activation that is independent of PKR and dsRNA. MERS-CoV p4a is a dsRNA binding protein. Mutation of the dsRNA binding motif in p4a disrupted its PKR antagonistic activity. By inserting p4a in a picornavirus lacking its natural PKR antagonist, we showed that p4a exerts PKR antagonistic activity also under infection conditions. However, a recombinant MERS-CoV deficient in p4a expression still suppressed SG formation, indicating the expression of at least one other stress response antagonist. This virus also suppressed the dsRNA-independent stress response pathway. Thus, MERS-CoV interferes with antiviral stress responses using at least two different mechanisms, with p4a suppressing the PKR-dependent stress response pathway, probably by sequestering dsRNA. MERS-CoV p4a represents the first coronavirus stress response antagonist described.</p>
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<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS Pathog</journal-id>
<journal-id journal-id-type="iso-abbrev">PLoS Pathog</journal-id>
<journal-id journal-id-type="publisher-id">plos</journal-id>
<journal-id journal-id-type="pmc">plospath</journal-id>
<journal-title-group><journal-title>PLoS Pathogens</journal-title>
</journal-title-group>
<issn pub-type="ppub">1553-7366</issn>
<issn pub-type="epub">1553-7374</issn>
<publisher><publisher-name>Public Library of Science</publisher-name>
<publisher-loc>San Francisco, CA USA</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">27783669</article-id>
<article-id pub-id-type="pmc">5081173</article-id>
<article-id pub-id-type="doi">10.1371/journal.ppat.1005982</article-id>
<article-id pub-id-type="publisher-id">PPATHOGENS-D-16-01222</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Biology and life sciences</subject>
<subj-group><subject>Organisms</subject>
<subj-group><subject>Viruses</subject>
<subj-group><subject>RNA viruses</subject>
<subj-group><subject>Coronaviruses</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject>
<subj-group><subject>Microbiology</subject>
<subj-group><subject>Medical Microbiology</subject>
<subj-group><subject>Microbial Pathogens</subject>
<subj-group><subject>Viral Pathogens</subject>
<subj-group><subject>Coronaviruses</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject>
<subj-group><subject>Pathology and Laboratory Medicine</subject>
<subj-group><subject>Pathogens</subject>
<subj-group><subject>Microbial Pathogens</subject>
<subj-group><subject>Viral Pathogens</subject>
<subj-group><subject>Coronaviruses</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject>
<subj-group><subject>Organisms</subject>
<subj-group><subject>Viruses</subject>
<subj-group><subject>Viral Pathogens</subject>
<subj-group><subject>Coronaviruses</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject>
<subj-group><subject>Cell Biology</subject>
<subj-group><subject>Cell Processes</subject>
<subj-group><subject>Cellular Stress Responses</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject>
<subj-group><subject>Microbiology</subject>
<subj-group><subject>Virology</subject>
<subj-group><subject>Viral Replication</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject>
<subj-group><subject>Molecular Biology</subject>
<subj-group><subject>Molecular Biology Techniques</subject>
<subj-group><subject>Transfection</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Research and Analysis Methods</subject>
<subj-group><subject>Molecular Biology Techniques</subject>
<subj-group><subject>Transfection</subject>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject>
<subj-group><subject>Biochemistry</subject>
<subj-group><subject>Proteins</subject>
<subj-group><subject>Recombinant Proteins</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Research and Analysis Methods</subject>
<subj-group><subject>Imaging Techniques</subject>
<subj-group><subject>Fluorescence Imaging</subject>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject>
<subj-group><subject>Pulmonology</subject>
<subj-group><subject>Respiratory Infections</subject>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Biology and life sciences</subject>
<subj-group><subject>Molecular biology</subject>
<subj-group><subject>Molecular biology techniques</subject>
<subj-group><subject>DNA construction</subject>
<subj-group><subject>Plasmid Construction</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v3"><subject>Research and analysis methods</subject>
<subj-group><subject>Molecular biology techniques</subject>
<subj-group><subject>DNA construction</subject>
<subj-group><subject>Plasmid Construction</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</article-categories>
<title-group><article-title>Middle East Respiratory Coronavirus Accessory Protein 4a Inhibits PKR-Mediated Antiviral Stress Responses</article-title>
<alt-title alt-title-type="running-head">MERS-CoV Accessory Protein 4a Inhibits PKR-Mediated Stress Responses</alt-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Rabouw</surname>
<given-names>Huib H.</given-names>
</name>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author" equal-contrib="yes"><name><surname>Langereis</surname>
<given-names>Martijn A.</given-names>
</name>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author" equal-contrib="yes"><name><surname>Knaap</surname>
<given-names>Robert C. M.</given-names>
</name>
<xref ref-type="aff" rid="aff002"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0002-5916-7548</contrib-id>
<name><surname>Dalebout</surname>
<given-names>Tim J.</given-names>
</name>
<xref ref-type="aff" rid="aff002"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Canton</surname>
<given-names>Javier</given-names>
</name>
<xref ref-type="aff" rid="aff003"><sup>3</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Sola</surname>
<given-names>Isabel</given-names>
</name>
<xref ref-type="aff" rid="aff003"><sup>3</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Enjuanes</surname>
<given-names>Luis</given-names>
</name>
<xref ref-type="aff" rid="aff003"><sup>3</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bredenbeek</surname>
<given-names>Peter J.</given-names>
</name>
<xref ref-type="aff" rid="aff002"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kikkert</surname>
<given-names>Marjolein</given-names>
</name>
<xref ref-type="aff" rid="aff002"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>de Groot</surname>
<given-names>Raoul J.</given-names>
</name>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>van Kuppeveld</surname>
<given-names>Frank J. M.</given-names>
</name>
<xref ref-type="aff" rid="aff001"><sup>1</sup>
</xref>
<xref ref-type="corresp" rid="cor001">*</xref>
</contrib>
</contrib-group>
<aff id="aff001"><label>1</label>
<addr-line>Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands</addr-line>
</aff>
<aff id="aff002"><label>2</label>
<addr-line>Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands</addr-line>
</aff>
<aff id="aff003"><label>3</label>
<addr-line>Department of Molecular and Cell Biology, National Center of Biotechnology (CNB-CSIC), Campus Universidad Autonoma de Madrid, Madrid, Spain</addr-line>
</aff>
<contrib-group><contrib contrib-type="editor"><name><surname>Frieman</surname>
<given-names>Matthew B.</given-names>
</name>
<role>Editor</role>
<xref ref-type="aff" rid="edit1"></xref>
</contrib>
</contrib-group>
<aff id="edit1"><addr-line>University of Maryland School of Medicine, UNITED STATES</addr-line>
</aff>
<author-notes><fn fn-type="COI-statement" id="coi001"><p>The authors have declared that no competing interests exist.</p>
</fn>
<fn fn-type="con"><p><list list-type="simple"><list-item><p><bold>Conceptualization:</bold>
HHR MAL RJdG FJMvK.</p>
</list-item>
<list-item><p><bold>Formal analysis:</bold>
HHR.</p>
</list-item>
<list-item><p><bold>Funding acquisition:</bold>
MAL FJMvK.</p>
</list-item>
<list-item><p><bold>Investigation:</bold>
HHR MAL TJD RCMK PJB JC.</p>
</list-item>
<list-item><p><bold>Methodology:</bold>
HHR MAL RJdG FJMvK.</p>
</list-item>
<list-item><p><bold>Project administration:</bold>
FJMvK.</p>
</list-item>
<list-item><p><bold>Resources:</bold>
IS LE PJB MK.</p>
</list-item>
<list-item><p><bold>Supervision:</bold>
LE IS MK RJdG FJMvK.</p>
</list-item>
<list-item><p><bold>Validation:</bold>
HHR MAL RJdG FJMvK.</p>
</list-item>
<list-item><p><bold>Visualization:</bold>
HHR MAL FJMvK.</p>
</list-item>
<list-item><p><bold>Writing – original draft:</bold>
HHR MAL RJdG FJMvK.</p>
</list-item>
<list-item><p><bold>Writing – review & editing:</bold>
HHR MAL RJdG FJMvK.</p>
</list-item>
</list>
</p>
</fn>
<corresp id="cor001">* E-mail: <email>F.J.M.vanKuppeveld@uu.nl</email>
</corresp>
</author-notes>
<pub-date pub-type="epub"><day>26</day>
<month>10</month>
<year>2016</year>
</pub-date>
<pub-date pub-type="collection"><month>10</month>
<year>2016</year>
</pub-date>
<volume>12</volume>
<issue>10</issue>
<elocation-id>e1005982</elocation-id>
<history><date date-type="received"><day>1</day>
<month>6</month>
<year>2016</year>
</date>
<date date-type="accepted"><day>6</day>
<month>10</month>
<year>2016</year>
</date>
</history>
<permissions><copyright-statement>© 2016 Rabouw et al</copyright-statement>
<copyright-year>2016</copyright-year>
<copyright-holder>Rabouw et al</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.</license-p>
</license>
</permissions>
<self-uri content-type="pdf" xlink:href="ppat.1005982.pdf"></self-uri>
<abstract><p>Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe respiratory infections that can be life-threatening. To establish an infection and spread, MERS-CoV, like most other viruses, must navigate through an intricate network of antiviral host responses. Besides the well-known type I interferon (IFN-α/β) response, the protein kinase R (PKR)-mediated stress response is being recognized as an important innate response pathway. Upon detecting viral dsRNA, PKR phosphorylates eIF2α, leading to the inhibition of cellular and viral translation and the formation of stress granules (SGs), which are increasingly recognized as platforms for antiviral signaling pathways. It is unknown whether cellular infection by MERS-CoV activates the stress response pathway or whether the virus has evolved strategies to suppress this infection-limiting pathway. Here, we show that cellular infection with MERS-CoV does not lead to the formation of SGs. By transiently expressing the MERS-CoV accessory proteins individually, we identified a role of protein 4a (p4a) in preventing activation of the stress response pathway. Expression of MERS-CoV p4a impeded dsRNA-mediated PKR activation, thereby rescuing translation inhibition and preventing SG formation. In contrast, p4a failed to suppress stress response pathway activation that is independent of PKR and dsRNA. MERS-CoV p4a is a dsRNA binding protein. Mutation of the dsRNA binding motif in p4a disrupted its PKR antagonistic activity. By inserting p4a in a picornavirus lacking its natural PKR antagonist, we showed that p4a exerts PKR antagonistic activity also under infection conditions. However, a recombinant MERS-CoV deficient in p4a expression still suppressed SG formation, indicating the expression of at least one other stress response antagonist. This virus also suppressed the dsRNA-independent stress response pathway. Thus, MERS-CoV interferes with antiviral stress responses using at least two different mechanisms, with p4a suppressing the PKR-dependent stress response pathway, probably by sequestering dsRNA. MERS-CoV p4a represents the first coronavirus stress response antagonist described.</p>
</abstract>
<abstract abstract-type="summary"><title>Author Summary</title>
<p>Human coronaviruses generally cause relatively mild respiratory disease. In the past 15 years, the world has witnessed the emergence of two coronaviruses with high mortality rates in humans; severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, both originating from animal reservoirs. Successful infection of a host not only depends on the presence of an appropriate receptor but also on the ability of a virus to evade innate antiviral host responses, which constitute the first line of defense against invading viruses. MERS-CoV has been reported to actively suppress the IFN-α/β response, but it is unknown whether it also interferes with another important innate antiviral response, the stress response pathway. Activation of this pathway by a kinase, PKR, curtails virus infection by shutting off cellular and viral protein synthesis. To date, no coronavirus protein has been recognized to suppress the stress response pathway. Here, we show that the accessory protein 4a of MERS-CoV is a potent stress antagonist that prevents PKR activation by sequestering its ligand, dsRNA. This finding furthers our understanding of the molecular mechanism used by MERS-CoV to evade infection-limiting antiviral host responses and may provide new avenues for therapeutic intervention.</p>
</abstract>
<funding-group><award-group id="award001"><funding-source><institution>Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NL)</institution>
</funding-source>
<award-id>NWO-918.12.628</award-id>
<principal-award-recipient><name><surname>van Kuppeveld</surname>
<given-names>Frank J. M.</given-names>
</name>
</principal-award-recipient>
</award-group>
<award-group id="award002"><funding-source><institution>Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NL)</institution>
</funding-source>
<award-id>NWO-863.13.008</award-id>
<principal-award-recipient><name><surname>Langereis</surname>
<given-names>Martijn A.</given-names>
</name>
</principal-award-recipient>
</award-group>
<funding-statement>The work is supported by a Vici grant (NWO-918.12.628) from the Netherlands Organization for Scientific Research. MAL is supported by a Veni grant (NWO-863.13.008) from the Netherlands Organization for Scientific Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.</funding-statement>
</funding-group>
<counts><fig-count count="9"></fig-count>
<table-count count="0"></table-count>
<page-count count="26"></page-count>
</counts>
<custom-meta-group><custom-meta id="data-availability"><meta-name>Data Availability</meta-name>
<meta-value>All relevant data are within the paper and its Supporting Information files.</meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
<notes><title>Data Availability</title>
<p>All relevant data are within the paper and its Supporting Information files.</p>
</notes>
</front>
</pmc>
<affiliations><list><country><li>Espagne</li>
<li>Pays-Bas</li>
</country>
<region><li>Communauté de Madrid</li>
<li>Hollande-Méridionale</li>
<li>Utrecht (province)</li>
</region>
<settlement><li>Leyde</li>
<li>Madrid</li>
<li>Utrecht</li>
</settlement>
<orgName><li>Université d'Utrecht</li>
</orgName>
</list>
<tree><country name="Pays-Bas"><region name="Utrecht (province)"><name sortKey="Rabouw, Huib H" sort="Rabouw, Huib H" uniqKey="Rabouw H" first="Huib H." last="Rabouw">Huib H. Rabouw</name>
</region>
<name sortKey="Bredenbeek, Peter J" sort="Bredenbeek, Peter J" uniqKey="Bredenbeek P" first="Peter J." last="Bredenbeek">Peter J. Bredenbeek</name>
<name sortKey="Dalebout, Tim J" sort="Dalebout, Tim J" uniqKey="Dalebout T" first="Tim J." last="Dalebout">Tim J. Dalebout</name>
<name sortKey="De Groot, Raoul J" sort="De Groot, Raoul J" uniqKey="De Groot R" first="Raoul J." last="De Groot">Raoul J. De Groot</name>
<name sortKey="Kikkert, Marjolein" sort="Kikkert, Marjolein" uniqKey="Kikkert M" first="Marjolein" last="Kikkert">Marjolein Kikkert</name>
<name sortKey="Knaap, Robert C M" sort="Knaap, Robert C M" uniqKey="Knaap R" first="Robert C. M." last="Knaap">Robert C. M. Knaap</name>
<name sortKey="Langereis, Martijn A" sort="Langereis, Martijn A" uniqKey="Langereis M" first="Martijn A." last="Langereis">Martijn A. Langereis</name>
<name sortKey="Van Kuppeveld, Frank J M" sort="Van Kuppeveld, Frank J M" uniqKey="Van Kuppeveld F" first="Frank J. M." last="Van Kuppeveld">Frank J. M. Van Kuppeveld</name>
</country>
<country name="Espagne"><region name="Communauté de Madrid"><name sortKey="Canton, Javier" sort="Canton, Javier" uniqKey="Canton J" first="Javier" last="Canton">Javier Canton</name>
</region>
<name sortKey="Enjuanes, Luis" sort="Enjuanes, Luis" uniqKey="Enjuanes L" first="Luis" last="Enjuanes">Luis Enjuanes</name>
<name sortKey="Sola, Isabel" sort="Sola, Isabel" uniqKey="Sola I" first="Isabel" last="Sola">Isabel Sola</name>
</country>
</tree>
</affiliations>
</record>
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