Middle East Respiratory Coronavirus Accessory Protein 4a Inhibits PKR-Mediated Antiviral Stress Responses.
Identifieur interne : 000F25 ( PubMed/Corpus ); précédent : 000F24; suivant : 000F26Middle East Respiratory Coronavirus Accessory Protein 4a Inhibits PKR-Mediated Antiviral Stress Responses.
Auteurs : Huib H. Rabouw ; Martijn A. Langereis ; Robert C M. Knaap ; Tim J. Dalebout ; Javier Canton ; Isabel Sola ; Luis Enjuanes ; Peter J. Bredenbeek ; Marjolein Kikkert ; Raoul J. De Groot ; Frank J M. Van KuppeveldSource :
- PLoS pathogens [ 1553-7374 ] ; 2016.
English descriptors
- KwdEn :
- Blotting, Western, Cell Line, Coronavirus Infections (immunology), Coronavirus Infections (metabolism), Flow Cytometry, Fluorescent Antibody Technique, Gene Knockout Techniques, Humans, Immune Evasion (immunology), Inclusion Bodies, Viral (immunology), Inclusion Bodies, Viral (metabolism), Middle East Respiratory Syndrome Coronavirus (immunology), Middle East Respiratory Syndrome Coronavirus (metabolism), Polymerase Chain Reaction, Viral Regulatory and Accessory Proteins (immunology), Viral Regulatory and Accessory Proteins (metabolism), eIF-2 Kinase (immunology), eIF-2 Kinase (metabolism).
- MESH :
- chemical , immunology : Viral Regulatory and Accessory Proteins, eIF-2 Kinase.
- immunology : Coronavirus Infections, Immune Evasion, Inclusion Bodies, Viral, Middle East Respiratory Syndrome Coronavirus.
- metabolism : Coronavirus Infections, Inclusion Bodies, Viral, Middle East Respiratory Syndrome Coronavirus, Viral Regulatory and Accessory Proteins, eIF-2 Kinase.
- Blotting, Western, Cell Line, Flow Cytometry, Fluorescent Antibody Technique, Gene Knockout Techniques, Humans, Polymerase Chain Reaction.
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.
DOI: 10.1371/journal.ppat.1005982
PubMed: 27783669
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pubmed:27783669Le document en format XML
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Langereis</name><affiliation><nlm:affiliation>Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.</nlm:affiliation></affiliation></author><author><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><affiliation><nlm:affiliation>Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands.</nlm:affiliation></affiliation></author><author><name sortKey="Dalebout, Tim J" sort="Dalebout, Tim J" uniqKey="Dalebout T" first="Tim J" last="Dalebout">Tim J. 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Rabouw</name><affiliation><nlm:affiliation>Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.</nlm:affiliation></affiliation></author><author><name sortKey="Langereis, Martijn A" sort="Langereis, Martijn A" uniqKey="Langereis M" first="Martijn A" last="Langereis">Martijn A. Langereis</name><affiliation><nlm:affiliation>Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.</nlm:affiliation></affiliation></author><author><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><affiliation><nlm:affiliation>Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands.</nlm:affiliation></affiliation></author><author><name sortKey="Dalebout, Tim J" sort="Dalebout, Tim J" uniqKey="Dalebout T" first="Tim J" last="Dalebout">Tim J. Dalebout</name><affiliation><nlm:affiliation>Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands.</nlm:affiliation></affiliation></author><author><name sortKey="Canton, Javier" sort="Canton, Javier" uniqKey="Canton J" first="Javier" last="Canton">Javier Canton</name><affiliation><nlm:affiliation>Department of Molecular and Cell Biology, National Center of Biotechnology (CNB-CSIC), Campus Universidad Autonoma de Madrid, Madrid, Spain.</nlm:affiliation></affiliation></author><author><name sortKey="Sola, Isabel" sort="Sola, Isabel" uniqKey="Sola I" first="Isabel" last="Sola">Isabel Sola</name><affiliation><nlm:affiliation>Department of Molecular and Cell Biology, National Center of Biotechnology (CNB-CSIC), Campus Universidad Autonoma de Madrid, Madrid, Spain.</nlm:affiliation></affiliation></author><author><name sortKey="Enjuanes, Luis" sort="Enjuanes, Luis" uniqKey="Enjuanes L" first="Luis" last="Enjuanes">Luis Enjuanes</name><affiliation><nlm:affiliation>Department of Molecular and Cell Biology, National Center of Biotechnology (CNB-CSIC), Campus Universidad Autonoma de Madrid, Madrid, Spain.</nlm:affiliation></affiliation></author><author><name sortKey="Bredenbeek, Peter J" sort="Bredenbeek, Peter J" uniqKey="Bredenbeek P" first="Peter J" last="Bredenbeek">Peter J. Bredenbeek</name><affiliation><nlm:affiliation>Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands.</nlm:affiliation></affiliation></author><author><name sortKey="Kikkert, Marjolein" sort="Kikkert, Marjolein" uniqKey="Kikkert M" first="Marjolein" last="Kikkert">Marjolein Kikkert</name><affiliation><nlm:affiliation>Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands.</nlm:affiliation></affiliation></author><author><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><affiliation><nlm:affiliation>Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.</nlm:affiliation></affiliation></author><author><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><affiliation><nlm:affiliation>Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.</nlm:affiliation></affiliation></author></analytic><series><title level="j">PLoS pathogens</title><idno type="eISSN">1553-7374</idno><imprint><date when="2016" type="published">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Blotting, Western</term><term>Cell Line</term><term>Coronavirus Infections (immunology)</term><term>Coronavirus Infections (metabolism)</term><term>Flow Cytometry</term><term>Fluorescent Antibody Technique</term><term>Gene Knockout Techniques</term><term>Humans</term><term>Immune Evasion (immunology)</term><term>Inclusion Bodies, Viral (immunology)</term><term>Inclusion Bodies, Viral (metabolism)</term><term>Middle East Respiratory Syndrome Coronavirus (immunology)</term><term>Middle East Respiratory Syndrome Coronavirus (metabolism)</term><term>Polymerase Chain Reaction</term><term>Viral Regulatory and Accessory Proteins (immunology)</term><term>Viral Regulatory and Accessory Proteins (metabolism)</term><term>eIF-2 Kinase (immunology)</term><term>eIF-2 Kinase (metabolism)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="immunology" xml:lang="en"><term>Viral Regulatory and Accessory Proteins</term><term>eIF-2 Kinase</term></keywords><keywords scheme="MESH" qualifier="immunology" xml:lang="en"><term>Coronavirus Infections</term><term>Immune Evasion</term><term>Inclusion Bodies, Viral</term><term>Middle East Respiratory Syndrome Coronavirus</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Coronavirus Infections</term><term>Inclusion Bodies, Viral</term><term>Middle East Respiratory Syndrome Coronavirus</term><term>Viral Regulatory and Accessory Proteins</term><term>eIF-2 Kinase</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Blotting, Western</term><term>Cell Line</term><term>Flow Cytometry</term><term>Fluorescent Antibody Technique</term><term>Gene Knockout Techniques</term><term>Humans</term><term>Polymerase Chain Reaction</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">27783669</PMID><DateCompleted><Year>2017</Year><Month>05</Month><Day>19</Day></DateCompleted><DateRevised><Year>2019</Year><Month>02</Month><Day>02</Day></DateRevised><Article PubModel="Electronic-eCollection"><Journal><ISSN IssnType="Electronic">1553-7374</ISSN><JournalIssue CitedMedium="Internet"><Volume>12</Volume><Issue>10</Issue><PubDate><Year>2016</Year><Month>Oct</Month></PubDate></JournalIssue><Title>PLoS pathogens</Title><ISOAbbreviation>PLoS Pathog.</ISOAbbreviation></Journal><ArticleTitle>Middle East Respiratory Coronavirus Accessory Protein 4a Inhibits PKR-Mediated Antiviral Stress Responses.</ArticleTitle><Pagination><MedlinePgn>e1005982</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1371/journal.ppat.1005982</ELocationID><Abstract><AbstractText>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.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Rabouw</LastName><ForeName>Huib H</ForeName><Initials>HH</Initials><AffiliationInfo><Affiliation>Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Langereis</LastName><ForeName>Martijn A</ForeName><Initials>MA</Initials><AffiliationInfo><Affiliation>Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Knaap</LastName><ForeName>Robert C M</ForeName><Initials>RC</Initials><AffiliationInfo><Affiliation>Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Dalebout</LastName><ForeName>Tim J</ForeName><Initials>TJ</Initials><Identifier Source="ORCID">http://orcid.org/0000-0002-5916-7548</Identifier><AffiliationInfo><Affiliation>Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Canton</LastName><ForeName>Javier</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Department of Molecular and Cell Biology, National Center of Biotechnology (CNB-CSIC), Campus Universidad Autonoma de Madrid, Madrid, Spain.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Sola</LastName><ForeName>Isabel</ForeName><Initials>I</Initials><AffiliationInfo><Affiliation>Department of Molecular and Cell Biology, National Center of Biotechnology (CNB-CSIC), Campus Universidad Autonoma de Madrid, Madrid, Spain.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Enjuanes</LastName><ForeName>Luis</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>Department of Molecular and Cell Biology, National Center of Biotechnology (CNB-CSIC), Campus Universidad Autonoma de Madrid, Madrid, Spain.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bredenbeek</LastName><ForeName>Peter J</ForeName><Initials>PJ</Initials><AffiliationInfo><Affiliation>Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kikkert</LastName><ForeName>Marjolein</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>de Groot</LastName><ForeName>Raoul J</ForeName><Initials>RJ</Initials><AffiliationInfo><Affiliation>Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>van Kuppeveld</LastName><ForeName>Frank J M</ForeName><Initials>FJ</Initials><AffiliationInfo><Affiliation>Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2016</Year><Month>10</Month><Day>26</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>PLoS Pathog</MedlineTA><NlmUniqueID>101238921</NlmUniqueID><ISSNLinking>1553-7366</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D054334">Viral Regulatory and Accessory Proteins</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.11.1</RegistryNumber><NameOfSubstance UI="D019892">eIF-2 Kinase</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D015153" MajorTopicYN="N">Blotting, Western</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D002460" MajorTopicYN="N">Cell Line</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D018352" MajorTopicYN="N">Coronavirus Infections</DescriptorName><QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005434" MajorTopicYN="N">Flow Cytometry</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005455" MajorTopicYN="N">Fluorescent Antibody Technique</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D055786" MajorTopicYN="N">Gene Knockout Techniques</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D057131" MajorTopicYN="N">Immune Evasion</DescriptorName><QualifierName UI="Q000276" MajorTopicYN="Y">immunology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D007181" MajorTopicYN="N">Inclusion Bodies, Viral</DescriptorName><QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D065207" MajorTopicYN="N">Middle East Respiratory Syndrome Coronavirus</DescriptorName><QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D016133" MajorTopicYN="N">Polymerase Chain Reaction</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D054334" MajorTopicYN="N">Viral Regulatory and Accessory Proteins</DescriptorName><QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D019892" MajorTopicYN="N">eIF-2 Kinase</DescriptorName><QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading></MeshHeadingList><CoiStatement>The authors have declared that no competing interests exist.</CoiStatement></MedlineCitation><PubmedData><History><PubMedPubDate 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