MERS-CoV 4b protein interferes with the NF-κB-dependent innate immune response during infection
Identifieur interne : 000914 ( Main/Exploration ); précédent : 000913; suivant : 000915MERS-CoV 4b protein interferes with the NF-κB-dependent innate immune response during infection
Auteurs : Javier Canton [Espagne] ; Anthony R. Fehr [États-Unis] ; Raúl Fernandez-Delgado [Espagne] ; Francisco J. Gutierrez-Alvarez [Espagne] ; Maria T. Sanchez-Aparicio [États-Unis] ; Adolfo García-Sastre [États-Unis] ; Stanley Perlman [États-Unis] ; Luis Enjuanes [Espagne] ; Isabel Sola [Espagne]Source :
- PLoS Pathogens [ 1553-7366 ] ; 2018.
Descripteurs français
- KwdFr :
- Animaux, Cellules cultivées, Coronavirus du syndrome respiratoire du Moyen-Orient (immunologie), Coronavirus du syndrome respiratoire du Moyen-Orient (physiologie), Cricetinae, Facteur de transcription NF-kappa B (métabolisme), Facteur de transcription NF-kappa B (physiologie), Humains, Immunité innée (physiologie), Infections à coronavirus (immunologie), Infections à coronavirus (virologie), Interactions hôte-pathogène (immunologie), Protéines virales (physiologie), Échappement immunitaire.
- MESH :
- immunologie : Coronavirus du syndrome respiratoire du Moyen-Orient, Infections à coronavirus, Interactions hôte-pathogène.
- métabolisme : Facteur de transcription NF-kappa B.
- physiologie : Coronavirus du syndrome respiratoire du Moyen-Orient, Facteur de transcription NF-kappa B, Immunité innée, Protéines virales.
- virologie : Infections à coronavirus.
- Animaux, Cellules cultivées, Cricetinae, Humains, Échappement immunitaire.
English descriptors
- KwdEn :
- Animals, Cells, Cultured, Coronavirus Infections (immunology), Coronavirus Infections (virology), Cricetinae, Host-Pathogen Interactions (immunology), Humans, Immune Evasion, Immunity, Innate (physiology), Middle East Respiratory Syndrome Coronavirus (immunology), Middle East Respiratory Syndrome Coronavirus (physiology), NF-kappa B (metabolism), NF-kappa B (physiology), Viral Proteins (physiology).
- MESH :
- chemical , metabolism : NF-kappa B.
- immunology : Coronavirus Infections, Host-Pathogen Interactions, Middle East Respiratory Syndrome Coronavirus.
- physiology : Immunity, Innate, Middle East Respiratory Syndrome Coronavirus, NF-kappa B, Viral Proteins.
- virology : Coronavirus Infections.
- Animals, Cells, Cultured, Cricetinae, Humans, Immune Evasion.
Abstract
Middle East respiratory syndrome coronavirus (MERS-CoV) is a novel human coronavirus that emerged in 2012, causing severe pneumonia and acute respiratory distress syndrome (ARDS), with a case fatality rate of ~36%. When expressed in isolation, CoV accessory proteins have been shown to interfere with innate antiviral signaling pathways. However, there is limited information on the specific contribution of MERS-CoV accessory protein 4b to the repression of the innate antiviral response in the context of infection. We found that MERS-CoV 4b was required to prevent a robust NF-κB dependent response during infection. In wild-type virus infected cells, 4b localized to the nucleus, while NF-κB was retained in the cytoplasm. In contrast, in the absence of 4b or in the presence of cytoplasmic 4b mutants lacking a nuclear localization signal (NLS), NF-κB was translocated to the nucleus leading to the expression of pro-inflammatory cytokines. This indicates that NF-κB repression required the nuclear import of 4b mediated by a specific NLS. Interestingly, we also found that both in isolation and during infection, 4b interacted with α-karyopherin proteins in an NLS-dependent manner. In particular, 4b had a strong preference for binding karyopherin-α4 (KPNA4), which is known to translocate the NF-κB protein complex into the nucleus. Binding of 4b to KPNA4 during infection inhibited its interaction with NF-κB-p65 subunit. Thereby we propose a model where 4b outcompetes NF-κB for KPNA4 binding and translocation into the nucleus as a mechanism of interference with the NF-κB-mediated innate immune response.
Url:
DOI: 10.1371/journal.ppat.1006838
PubMed: 29370303
PubMed Central: 5800688
Affiliations:
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Madrid</region></placeName></affiliation></author><author><name sortKey="Fehr, Anthony R" sort="Fehr, Anthony R" uniqKey="Fehr A" first="Anthony R." last="Fehr">Anthony R. Fehr</name><affiliation wicri:level="2"><nlm:aff id="aff002"><addr-line>Department of Microbiology and Immunology, University of Iowa Carver College of Medicine, Iowa City, IA, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Microbiology and Immunology, University of Iowa Carver College of Medicine, Iowa City, IA</wicri:regionArea><placeName><region type="state">Iowa</region></placeName></affiliation></author><author><name sortKey="Fernandez Delgado, Raul" sort="Fernandez Delgado, Raul" uniqKey="Fernandez Delgado R" first="Raúl" last="Fernandez-Delgado">Raúl Fernandez-Delgado</name><affiliation wicri:level="3"><nlm:aff id="aff001"><addr-line>Department of Molecular and Cell Biology, Centro Nacional de Biotecnología (CNB-CSIC), Madrid, Spain</addr-line></nlm:aff><country xml:lang="fr">Espagne</country><wicri:regionArea>Department of Molecular and Cell Biology, Centro Nacional de Biotecnología (CNB-CSIC), Madrid</wicri:regionArea><placeName><settlement type="city">Madrid</settlement><region nuts="2" type="region">Communauté de Madrid</region></placeName></affiliation></author><author><name sortKey="Gutierrez Alvarez, Francisco J" sort="Gutierrez Alvarez, Francisco J" uniqKey="Gutierrez Alvarez F" first="Francisco J." last="Gutierrez-Alvarez">Francisco J. Gutierrez-Alvarez</name><affiliation wicri:level="3"><nlm:aff id="aff001"><addr-line>Department of Molecular and Cell Biology, Centro Nacional de Biotecnología (CNB-CSIC), Madrid, Spain</addr-line></nlm:aff><country xml:lang="fr">Espagne</country><wicri:regionArea>Department of Molecular and Cell Biology, Centro Nacional de Biotecnología (CNB-CSIC), Madrid</wicri:regionArea><placeName><settlement type="city">Madrid</settlement><region nuts="2" type="region">Communauté de Madrid</region></placeName></affiliation></author><author><name sortKey="Sanchez Aparicio, Maria T" sort="Sanchez Aparicio, Maria T" uniqKey="Sanchez Aparicio M" first="Maria T." last="Sanchez-Aparicio">Maria T. Sanchez-Aparicio</name><affiliation wicri:level="2"><nlm:aff id="aff003"><addr-line>Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation><affiliation wicri:level="2"><nlm:aff id="aff004"><addr-line>Global Health and Emerging Pathogens Institute. Icahn School of Medicine at Mount Sinai, New York, NY, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Global Health and Emerging Pathogens Institute. Icahn School of Medicine at Mount Sinai, New York, NY</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Garcia Sastre, Adolfo" sort="Garcia Sastre, Adolfo" uniqKey="Garcia Sastre A" first="Adolfo" last="García-Sastre">Adolfo García-Sastre</name><affiliation wicri:level="2"><nlm:aff id="aff003"><addr-line>Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation><affiliation wicri:level="2"><nlm:aff id="aff004"><addr-line>Global Health and Emerging Pathogens Institute. Icahn School of Medicine at Mount Sinai, New York, NY, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Global Health and Emerging Pathogens Institute. Icahn School of Medicine at Mount Sinai, New York, NY</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation><affiliation wicri:level="2"><nlm:aff id="aff005"><addr-line>Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Perlman, Stanley" sort="Perlman, Stanley" uniqKey="Perlman S" first="Stanley" last="Perlman">Stanley Perlman</name><affiliation wicri:level="2"><nlm:aff id="aff002"><addr-line>Department of Microbiology and Immunology, University of Iowa Carver College of Medicine, Iowa City, IA, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Microbiology and Immunology, University of Iowa Carver College of Medicine, Iowa City, IA</wicri:regionArea><placeName><region type="state">Iowa</region></placeName></affiliation></author><author><name sortKey="Enjuanes, Luis" sort="Enjuanes, Luis" uniqKey="Enjuanes L" first="Luis" last="Enjuanes">Luis Enjuanes</name><affiliation wicri:level="3"><nlm:aff id="aff001"><addr-line>Department of Molecular and Cell Biology, Centro Nacional de Biotecnología (CNB-CSIC), Madrid, Spain</addr-line></nlm:aff><country xml:lang="fr">Espagne</country><wicri:regionArea>Department of Molecular and Cell Biology, Centro Nacional de Biotecnología (CNB-CSIC), Madrid</wicri:regionArea><placeName><settlement type="city">Madrid</settlement><region nuts="2" type="region">Communauté de Madrid</region></placeName></affiliation></author><author><name sortKey="Sola, Isabel" sort="Sola, Isabel" uniqKey="Sola I" first="Isabel" last="Sola">Isabel Sola</name><affiliation wicri:level="3"><nlm:aff id="aff001"><addr-line>Department of Molecular and Cell Biology, Centro Nacional de Biotecnología (CNB-CSIC), Madrid, Spain</addr-line></nlm:aff><country xml:lang="fr">Espagne</country><wicri:regionArea>Department of Molecular and Cell Biology, Centro Nacional de Biotecnología (CNB-CSIC), Madrid</wicri:regionArea><placeName><settlement type="city">Madrid</settlement><region nuts="2" type="region">Communauté de Madrid</region></placeName></affiliation></author></analytic><series><title level="j">PLoS Pathogens</title><idno type="ISSN">1553-7366</idno><idno type="eISSN">1553-7374</idno><imprint><date when="2018">2018</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Cells, Cultured</term><term>Coronavirus Infections (immunology)</term><term>Coronavirus Infections (virology)</term><term>Cricetinae</term><term>Host-Pathogen Interactions (immunology)</term><term>Humans</term><term>Immune Evasion</term><term>Immunity, Innate (physiology)</term><term>Middle East Respiratory Syndrome Coronavirus (immunology)</term><term>Middle East Respiratory Syndrome Coronavirus (physiology)</term><term>NF-kappa B (metabolism)</term><term>NF-kappa B (physiology)</term><term>Viral Proteins (physiology)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term><term>Cellules cultivées</term><term>Coronavirus du syndrome respiratoire du Moyen-Orient (immunologie)</term><term>Coronavirus du syndrome respiratoire du Moyen-Orient (physiologie)</term><term>Cricetinae</term><term>Facteur de transcription NF-kappa B (métabolisme)</term><term>Facteur de transcription NF-kappa B (physiologie)</term><term>Humains</term><term>Immunité innée (physiologie)</term><term>Infections à coronavirus (immunologie)</term><term>Infections à coronavirus (virologie)</term><term>Interactions hôte-pathogène (immunologie)</term><term>Protéines virales (physiologie)</term><term>Échappement immunitaire</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>NF-kappa B</term></keywords><keywords scheme="MESH" qualifier="immunologie" xml:lang="fr"><term>Coronavirus du syndrome respiratoire du Moyen-Orient</term><term>Infections à coronavirus</term><term>Interactions hôte-pathogène</term></keywords><keywords scheme="MESH" qualifier="immunology" xml:lang="en"><term>Coronavirus Infections</term><term>Host-Pathogen Interactions</term><term>Middle East Respiratory Syndrome Coronavirus</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Facteur de transcription NF-kappa B</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Coronavirus du syndrome respiratoire du Moyen-Orient</term><term>Facteur de transcription NF-kappa B</term><term>Immunité innée</term><term>Protéines virales</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Immunity, Innate</term><term>Middle East Respiratory Syndrome Coronavirus</term><term>NF-kappa B</term><term>Viral Proteins</term></keywords><keywords scheme="MESH" qualifier="virologie" xml:lang="fr"><term>Infections à coronavirus</term></keywords><keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>Coronavirus Infections</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Cells, Cultured</term><term>Cricetinae</term><term>Humans</term><term>Immune Evasion</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Cellules cultivées</term><term>Cricetinae</term><term>Humains</term><term>Échappement immunitaire</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Middle East respiratory syndrome coronavirus (MERS-CoV) is a novel human coronavirus that emerged in 2012, causing severe pneumonia and acute respiratory distress syndrome (ARDS), with a case fatality rate of ~36%. When expressed in isolation, CoV accessory proteins have been shown to interfere with innate antiviral signaling pathways. However, there is limited information on the specific contribution of MERS-CoV accessory protein 4b to the repression of the innate antiviral response in the context of infection. We found that MERS-CoV 4b was required to prevent a robust NF-κB dependent response during infection. In wild-type virus infected cells, 4b localized to the nucleus, while NF-κB was retained in the cytoplasm. In contrast, in the absence of 4b or in the presence of cytoplasmic 4b mutants lacking a nuclear localization signal (NLS), NF-κB was translocated to the nucleus leading to the expression of pro-inflammatory cytokines. This indicates that NF-κB repression required the nuclear import of 4b mediated by a specific NLS. Interestingly, we also found that both in isolation and during infection, 4b interacted with α-karyopherin proteins in an NLS-dependent manner. In particular, 4b had a strong preference for binding karyopherin-α4 (KPNA4), which is known to translocate the NF-κB protein complex into the nucleus. Binding of 4b to KPNA4 during infection inhibited its interaction with NF-κB-p65 subunit. Thereby we propose a model where 4b outcompetes NF-κB for KPNA4 binding and translocation into the nucleus as a mechanism of interference with the NF-κB-mediated innate immune response.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Zielecki, F" uniqKey="Zielecki F">F Zielecki</name></author><author><name sortKey="Weber, M" uniqKey="Weber M">M Weber</name></author><author><name sortKey="Eickmann, M" uniqKey="Eickmann M">M Eickmann</name></author><author><name sortKey="Spiegelberg, L" uniqKey="Spiegelberg L">L Spiegelberg</name></author><author><name sortKey="Zaki, Am" uniqKey="Zaki A">AM Zaki</name></author><author><name sortKey="Matrosovich, M" uniqKey="Matrosovich M">M Matrosovich</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chan, Rw" uniqKey="Chan R">RW Chan</name></author><author><name sortKey="Chan, Mc" uniqKey="Chan M">MC Chan</name></author><author><name sortKey="Agnihothram, S" 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sortKey="Yoshikawa, N" uniqKey="Yoshikawa N">N Yoshikawa</name></author><author><name sortKey="Popov, Vl" uniqKey="Popov V">VL Popov</name></author><author><name sortKey="Galindo, Cl" uniqKey="Galindo C">CL Galindo</name></author><author><name sortKey="Garner, Hr" uniqKey="Garner H">HR Garner</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Fehr, Ar" uniqKey="Fehr A">AR Fehr</name></author><author><name sortKey="Channappanavar, R" uniqKey="Channappanavar R">R Channappanavar</name></author><author><name sortKey="Jankevicius, G" uniqKey="Jankevicius G">G Jankevicius</name></author><author><name sortKey="Fett, C" uniqKey="Fett C">C Fett</name></author><author><name sortKey="Zhao, J" uniqKey="Zhao J">J Zhao</name></author><author><name sortKey="Athmer, J" uniqKey="Athmer J">J Athmer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Livak, Kj" uniqKey="Livak K">KJ Livak</name></author><author><name sortKey="Schmittgen, Td" uniqKey="Schmittgen T">TD Schmittgen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Suzuki, K" uniqKey="Suzuki K">K Suzuki</name></author><author><name sortKey="Bose, P" uniqKey="Bose P">P Bose</name></author><author><name sortKey="Leong Quong, Ryy" uniqKey="Leong Quong R">RYY Leong-Quong</name></author><author><name sortKey="Fujita, Dj" uniqKey="Fujita D">DJ Fujita</name></author><author><name sortKey="Riabowol, K" uniqKey="Riabowol K">K Riabowol</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>Espagne</li><li>États-Unis</li></country><region><li>Communauté de Madrid</li><li>Iowa</li><li>État de New York</li></region><settlement><li>Madrid</li></settlement></list><tree><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="Fernandez Delgado, Raul" sort="Fernandez Delgado, Raul" uniqKey="Fernandez Delgado R" first="Raúl" last="Fernandez-Delgado">Raúl Fernandez-Delgado</name><name sortKey="Gutierrez Alvarez, Francisco J" sort="Gutierrez Alvarez, Francisco J" uniqKey="Gutierrez Alvarez F" first="Francisco J." last="Gutierrez-Alvarez">Francisco J. Gutierrez-Alvarez</name><name sortKey="Sola, Isabel" sort="Sola, Isabel" uniqKey="Sola I" first="Isabel" last="Sola">Isabel Sola</name></country><country name="États-Unis"><region name="Iowa"><name sortKey="Fehr, Anthony R" sort="Fehr, Anthony R" uniqKey="Fehr A" first="Anthony R." last="Fehr">Anthony R. Fehr</name></region><name sortKey="Garcia Sastre, Adolfo" sort="Garcia Sastre, Adolfo" uniqKey="Garcia Sastre A" first="Adolfo" last="García-Sastre">Adolfo García-Sastre</name><name sortKey="Garcia Sastre, Adolfo" sort="Garcia Sastre, Adolfo" uniqKey="Garcia Sastre A" first="Adolfo" last="García-Sastre">Adolfo García-Sastre</name><name sortKey="Garcia Sastre, Adolfo" sort="Garcia Sastre, Adolfo" uniqKey="Garcia Sastre A" first="Adolfo" last="García-Sastre">Adolfo García-Sastre</name><name sortKey="Perlman, Stanley" sort="Perlman, Stanley" uniqKey="Perlman S" first="Stanley" last="Perlman">Stanley Perlman</name><name sortKey="Sanchez Aparicio, Maria T" sort="Sanchez Aparicio, Maria T" uniqKey="Sanchez Aparicio M" first="Maria T." last="Sanchez-Aparicio">Maria T. Sanchez-Aparicio</name><name sortKey="Sanchez Aparicio, Maria T" sort="Sanchez Aparicio, Maria T" uniqKey="Sanchez Aparicio M" first="Maria T." last="Sanchez-Aparicio">Maria T. 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