MERS-CoV 4b protein interferes with the NF-κB-dependent innate immune response during infection.
Identifieur interne : 000861 ( PubMed/Checkpoint ); précédent : 000860; suivant : 000862MERS-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 [ 1553-7374 ] ; 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.
DOI: 10.1371/journal.ppat.1006838
PubMed: 29370303
Affiliations:
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pubmed:29370303Le document en format XML
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<front><div type="abstract" xml:lang="en">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.</div>
</front>
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<Title>PLoS pathogens</Title>
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<ArticleTitle>MERS-CoV 4b protein interferes with the NF-κB-dependent innate immune response during infection.</ArticleTitle>
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<Abstract><AbstractText>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.</AbstractText>
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<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Canton</LastName>
<ForeName>Javier</ForeName>
<Initials>J</Initials>
<AffiliationInfo><Affiliation>Department of Molecular and Cell Biology, Centro Nacional de Biotecnología (CNB-CSIC), Madrid, Spain.</Affiliation>
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<Author ValidYN="Y"><LastName>Fehr</LastName>
<ForeName>Anthony R</ForeName>
<Initials>AR</Initials>
<AffiliationInfo><Affiliation>Department of Microbiology and Immunology, University of Iowa Carver College of Medicine, Iowa City, IA, United States of America.</Affiliation>
</AffiliationInfo>
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<Author ValidYN="Y"><LastName>Fernandez-Delgado</LastName>
<ForeName>Raúl</ForeName>
<Initials>R</Initials>
<AffiliationInfo><Affiliation>Department of Molecular and Cell Biology, Centro Nacional de Biotecnología (CNB-CSIC), Madrid, Spain.</Affiliation>
</AffiliationInfo>
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<Author ValidYN="Y"><LastName>Gutierrez-Alvarez</LastName>
<ForeName>Francisco J</ForeName>
<Initials>FJ</Initials>
<AffiliationInfo><Affiliation>Department of Molecular and Cell Biology, Centro Nacional de Biotecnología (CNB-CSIC), Madrid, Spain.</Affiliation>
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<AffiliationInfo><Affiliation>Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.</Affiliation>
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<AffiliationInfo><Affiliation>Global Health and Emerging Pathogens Institute. Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.</Affiliation>
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