The PDZ-Binding Motif of Severe Acute Respiratory Syndrome Coronavirus Envelope Protein Is a Determinant of Viral Pathogenesis
Identifieur interne : 001409 ( Pmc/Curation ); précédent : 001408; suivant : 001410The PDZ-Binding Motif of Severe Acute Respiratory Syndrome Coronavirus Envelope Protein Is a Determinant of Viral Pathogenesis
Auteurs : Jose M. Jimenez-Guarde O ; Jose L. Nieto-Torres ; Marta L. Dediego ; Jose A. Regla-Nava ; Raul Fernandez-Delgado ; Carlos Casta O-Rodriguez ; Luis EnjuanesSource :
- PLoS Pathogens [ 1553-7366 ] ; 2014.
Abstract
A recombinant severe acute respiratory syndrome coronavirus (SARS-CoV) lacking the envelope (E) protein is attenuated
Url:
DOI: 10.1371/journal.ppat.1004320
PubMed: 25122212
PubMed Central: 4133396
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">The PDZ-Binding Motif of Severe Acute Respiratory Syndrome Coronavirus Envelope Protein Is a Determinant of Viral Pathogenesis</title><author><name sortKey="Jimenez Guarde O, Jose M" sort="Jimenez Guarde O, Jose M" uniqKey="Jimenez Guarde O J" first="Jose M." last="Jimenez-Guarde O">Jose M. Jimenez-Guarde O</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Nieto Torres, Jose L" sort="Nieto Torres, Jose L" uniqKey="Nieto Torres J" first="Jose L." last="Nieto-Torres">Jose L. Nieto-Torres</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Dediego, Marta L" sort="Dediego, Marta L" uniqKey="Dediego M" first="Marta L." last="Dediego">Marta L. Dediego</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Regla Nava, Jose A" sort="Regla Nava, Jose A" uniqKey="Regla Nava J" first="Jose A." last="Regla-Nava">Jose A. Regla-Nava</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Fernandez Delgado, Raul" sort="Fernandez Delgado, Raul" uniqKey="Fernandez Delgado R" first="Raul" last="Fernandez-Delgado">Raul Fernandez-Delgado</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Casta O Rodriguez, Carlos" sort="Casta O Rodriguez, Carlos" uniqKey="Casta O Rodriguez C" first="Carlos" last="Casta O-Rodriguez">Carlos Casta O-Rodriguez</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Enjuanes, Luis" sort="Enjuanes, Luis" uniqKey="Enjuanes L" first="Luis" last="Enjuanes">Luis Enjuanes</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">25122212</idno><idno type="pmc">4133396</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4133396</idno><idno type="RBID">PMC:4133396</idno><idno type="doi">10.1371/journal.ppat.1004320</idno><date when="2014">2014</date><idno type="wicri:Area/Pmc/Corpus">001409</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001409</idno><idno type="wicri:Area/Pmc/Curation">001409</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">001409</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">The PDZ-Binding Motif of Severe Acute Respiratory Syndrome Coronavirus Envelope Protein Is a Determinant of Viral Pathogenesis</title><author><name sortKey="Jimenez Guarde O, Jose M" sort="Jimenez Guarde O, Jose M" uniqKey="Jimenez Guarde O J" first="Jose M." last="Jimenez-Guarde O">Jose M. Jimenez-Guarde O</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Nieto Torres, Jose L" sort="Nieto Torres, Jose L" uniqKey="Nieto Torres J" first="Jose L." last="Nieto-Torres">Jose L. Nieto-Torres</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Dediego, Marta L" sort="Dediego, Marta L" uniqKey="Dediego M" first="Marta L." last="Dediego">Marta L. Dediego</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Regla Nava, Jose A" sort="Regla Nava, Jose A" uniqKey="Regla Nava J" first="Jose A." last="Regla-Nava">Jose A. Regla-Nava</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Fernandez Delgado, Raul" sort="Fernandez Delgado, Raul" uniqKey="Fernandez Delgado R" first="Raul" last="Fernandez-Delgado">Raul Fernandez-Delgado</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Casta O Rodriguez, Carlos" sort="Casta O Rodriguez, Carlos" uniqKey="Casta O Rodriguez C" first="Carlos" last="Casta O-Rodriguez">Carlos Casta O-Rodriguez</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Enjuanes, Luis" sort="Enjuanes, Luis" uniqKey="Enjuanes L" first="Luis" last="Enjuanes">Luis Enjuanes</name><affiliation><nlm:aff id="aff1"></nlm:aff></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="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>A recombinant severe acute respiratory syndrome coronavirus (SARS-CoV) lacking the envelope (E) protein is attenuated <italic>in vivo</italic>. Here we report that E protein PDZ-binding motif (PBM), a domain involved in protein-protein interactions, is a major determinant of virulence. Elimination of SARS-CoV E protein PBM by using reverse genetics caused a reduction in the deleterious exacerbation of the immune response triggered during infection with the parental virus and virus attenuation. Cellular protein syntenin was identified to bind the E protein PBM during SARS-CoV infection by using three complementary strategies, yeast two-hybrid, reciprocal coimmunoprecipitation and confocal microscopy assays. Syntenin redistributed from the nucleus to the cell cytoplasm during infection with viruses containing the E protein PBM, activating p38 MAPK and leading to the overexpression of inflammatory cytokines. Silencing of syntenin using siRNAs led to a decrease in p38 MAPK activation in SARS-CoV infected cells, further reinforcing their functional relationship. Active p38 MAPK was reduced in lungs of mice infected with SARS-CoVs lacking E protein PBM as compared with the parental virus, leading to a decreased expression of inflammatory cytokines and to virus attenuation. Interestingly, administration of a p38 MAPK inhibitor led to an increase in mice survival after infection with SARS-CoV, confirming the relevance of this pathway in SARS-CoV virulence. Therefore, the E protein PBM is a virulence domain that activates immunopathology most likely by using syntenin as a mediator of p38 MAPK induced inflammation.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Peiris, Js" uniqKey="Peiris J">JS Peiris</name></author><author><name sortKey="Yuen, Ky" uniqKey="Yuen K">KY Yuen</name></author><author><name sortKey="Osterhaus, Ad" uniqKey="Osterhaus A">AD Osterhaus</name></author><author><name sortKey="Stohr, K" uniqKey="Stohr K">K Stohr</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lau, Sk" uniqKey="Lau S">SK Lau</name></author><author><name sortKey="Woo, Pc" uniqKey="Woo P">PC Woo</name></author><author><name sortKey="Li, Ks" uniqKey="Li K">KS Li</name></author><author><name sortKey="Huang, Y" uniqKey="Huang Y">Y Huang</name></author><author><name sortKey="Tsoi, Hw" uniqKey="Tsoi H">HW 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<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, USA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">25122212</article-id><article-id pub-id-type="pmc">4133396</article-id><article-id pub-id-type="publisher-id">PPATHOGENS-D-13-03246</article-id><article-id pub-id-type="doi">10.1371/journal.ppat.1004320</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="Discipline-v2"><subject>Biology and Life Sciences</subject><subj-group><subject>Immunology</subject><subj-group><subject>Clinical Immunology</subject><subj-group><subject>Immunopathology</subject></subj-group></subj-group><subj-group><subject>Immune Response</subject><subj-group><subject>Inflammation</subject></subj-group></subj-group><subj-group><subject>Immune System</subject><subj-group><subject>Innate Immune System</subject></subj-group></subj-group><subj-group><subject>Immunity</subject></subj-group></subj-group><subj-group><subject>Microbiology</subject><subj-group><subject>Virology</subject></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v2"><subject>Medicine and Health Sciences</subject><subj-group><subject>Infectious Diseases</subject><subj-group><subject>Emerging Infectious Diseases</subject></subj-group></subj-group><subj-group><subject>Pathology and Laboratory Medicine</subject><subj-group><subject>Pathogenesis</subject><subj-group><subject>Host-Pathogen Interactions</subject></subj-group></subj-group><subj-group><subject>Pathogens</subject><subj-group><subject>Virulence Factors</subject></subj-group></subj-group></subj-group></subj-group></article-categories><title-group><article-title>The PDZ-Binding Motif of Severe Acute Respiratory Syndrome Coronavirus Envelope Protein Is a Determinant of Viral Pathogenesis</article-title><alt-title alt-title-type="running-head">SARS-CoV E Protein PDZ-Binding Motif and Virulence</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Jimenez-Guardeño</surname><given-names>Jose M.</given-names></name><xref ref-type="aff" rid="aff1"></xref></contrib><contrib contrib-type="author"><name><surname>Nieto-Torres</surname><given-names>Jose L.</given-names></name><xref ref-type="aff" rid="aff1"></xref></contrib><contrib contrib-type="author"><name><surname>DeDiego</surname><given-names>Marta L.</given-names></name><xref ref-type="aff" rid="aff1"></xref><xref ref-type="author-notes" rid="fn1"><sup>¤</sup></xref></contrib><contrib contrib-type="author"><name><surname>Regla-Nava</surname><given-names>Jose A.</given-names></name><xref ref-type="aff" rid="aff1"></xref></contrib><contrib contrib-type="author"><name><surname>Fernandez-Delgado</surname><given-names>Raul</given-names></name><xref ref-type="aff" rid="aff1"></xref></contrib><contrib contrib-type="author"><name><surname>Castaño-Rodriguez</surname><given-names>Carlos</given-names></name><xref ref-type="aff" rid="aff1"></xref></contrib><contrib contrib-type="author"><name><surname>Enjuanes</surname><given-names>Luis</given-names></name><xref ref-type="aff" rid="aff1"></xref><xref ref-type="corresp" rid="cor1"><sup>*</sup></xref></contrib></contrib-group><aff id="aff1"><addr-line>Department of Molecular and Cell Biology, Centro Nacional de Biotecnología (CNB-CSIC), Darwin 3, Campus Universidad Autónoma de Madrid, Madrid, Spain</addr-line></aff><contrib-group><contrib contrib-type="editor"><name><surname>Basler</surname><given-names>Christopher F.</given-names></name><role>Editor</role><xref ref-type="aff" rid="edit1"></xref></contrib></contrib-group><aff id="edit1"><addr-line>Mount Sinai School of Medicine, United States of America</addr-line></aff><author-notes><corresp id="cor1">* E-mail: <email>L.Enjuanes@cnb.csic.es</email></corresp><fn fn-type="COI-statement"><p>The authors have declared that no competing interests exist.</p></fn><fn fn-type="con"><p>Conceived and designed the experiments: JMJG JLNT MLD LE. Performed the experiments: JMJG JLNT MLD JARN RFD. Analyzed the data: JMJG JLNT MLD JARN LE. Contributed reagents/materials/analysis tools: JMJG JLNT MLD JARN RFD CCR LE. Wrote the paper: JMJG JLNT MLD JARN CCR LE.</p></fn><fn id="fn1" fn-type="current-aff"><label>¤</label><p>Current address: David H. Smith Center for Vaccine Biology and Immunology, University of Rochester Medical Center, Rochester, New York, United States of America</p></fn></author-notes><pub-date pub-type="collection"><month>8</month><year>2014</year></pub-date><pub-date pub-type="epub"><day>14</day><month>8</month><year>2014</year></pub-date><volume>10</volume><issue>8</issue><elocation-id>e1004320</elocation-id><history><date date-type="received"><day>10</day><month>12</month><year>2013</year></date><date date-type="accepted"><day>8</day><month>7</month><year>2014</year></date></history><permissions><copyright-statement>© 2014 Jimenez-Guardeño et al</copyright-statement><copyright-year>2014</copyright-year><copyright-holder>Jimenez-Guardeño 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><abstract><p>A recombinant severe acute respiratory syndrome coronavirus (SARS-CoV) lacking the envelope (E) protein is attenuated <italic>in vivo</italic>. Here we report that E protein PDZ-binding motif (PBM), a domain involved in protein-protein interactions, is a major determinant of virulence. Elimination of SARS-CoV E protein PBM by using reverse genetics caused a reduction in the deleterious exacerbation of the immune response triggered during infection with the parental virus and virus attenuation. Cellular protein syntenin was identified to bind the E protein PBM during SARS-CoV infection by using three complementary strategies, yeast two-hybrid, reciprocal coimmunoprecipitation and confocal microscopy assays. Syntenin redistributed from the nucleus to the cell cytoplasm during infection with viruses containing the E protein PBM, activating p38 MAPK and leading to the overexpression of inflammatory cytokines. Silencing of syntenin using siRNAs led to a decrease in p38 MAPK activation in SARS-CoV infected cells, further reinforcing their functional relationship. Active p38 MAPK was reduced in lungs of mice infected with SARS-CoVs lacking E protein PBM as compared with the parental virus, leading to a decreased expression of inflammatory cytokines and to virus attenuation. Interestingly, administration of a p38 MAPK inhibitor led to an increase in mice survival after infection with SARS-CoV, confirming the relevance of this pathway in SARS-CoV virulence. Therefore, the E protein PBM is a virulence domain that activates immunopathology most likely by using syntenin as a mediator of p38 MAPK induced inflammation.</p></abstract><abstract abstract-type="summary"><title>Author Summary</title><p>SARS-CoV caused a worldwide epidemic infecting 8000 people with a mortality of about 10%. A recombinant SARS-CoV lacking the E protein was attenuated <italic>in vivo</italic>. The E protein contains a PDZ-binding motif (PBM), a domain potentially involved in the interaction with more than 400 cellular proteins, which highlights its relevance in modulating host-cell behavior. To analyze the contributions of this motif to virulence, recombinant viruses with or without E protein PBM were generated. Recombinant SARS-CoVs lacking E protein PBM caused minimal lung damage and were attenuated, in contrast to viruses containing this motif, indicating that E protein PBM is a virulence determinant. E protein PBM induces the deleterious exacerbated immune response triggered during SARS-CoV infection, and interacts with the cellular protein syntenin, as demonstrated using proteomic analyses. Interestingly, syntenin redistributed from nucleus to cytoplasm during SARS-CoV infection, activating p38 MAPK and triggering the overexpression of inflammatory cytokines. Furthermore, silencing of syntenin using siRNAs led to a decrease in p38 MAPK activation. In addition, administration of a p38 MAPK inhibitor led to an increase in mice survival after SARS-CoV infection. These results indicate that syntenin and p38 MAPK are potential therapeutic targets to reduce the exacerbated immune response during SARS-CoV infection.</p></abstract><funding-group><funding-statement>This work was supported by grants from the government of Spain (BIO2010-16705), the European Community's Seventh Framework Programme (FP7/2007-2013) under the project “EMPERIE” EC Gran Agreement number 223498, and U.S. National Institutes of Health (NIH) (2P01AI060699, 0258-3413/HHSN266200700010C). JMJG received a JAE fellowship from the CSIC-JAE Program co-funded by the European Social Fund. JARN and CCR received a contract from Fundación La Caixa. 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><page-count count="20"></page-count></counts></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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