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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">ID: 203</title><author><name sortKey="Jha, Babal K" sort="Jha, Babal K" uniqKey="Jha B" first="Babal K." last="Jha">Babal K. Jha</name><affiliation><nlm:aff id="af005">Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA</nlm:aff></affiliation></author><author><name sortKey="Thornbrough, Joshua M" sort="Thornbrough, Joshua M" uniqKey="Thornbrough J" first="Joshua M." last="Thornbrough">Joshua M. Thornbrough</name><affiliation><nlm:aff id="af010">Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA</nlm:aff></affiliation></author><author><name sortKey="Goldstein, Stephen A" sort="Goldstein, Stephen A" uniqKey="Goldstein S" first="Stephen A." last="Goldstein">Stephen A. Goldstein</name><affiliation><nlm:aff id="af010">Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA</nlm:aff></affiliation></author><author><name sortKey="Elliott, Ruth" sort="Elliott, Ruth" uniqKey="Elliott R" first="Ruth" last="Elliott">Ruth Elliott</name><affiliation><nlm:aff id="af010">Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA</nlm:aff></affiliation></author><author><name sortKey="Weiss, Susan R" sort="Weiss, Susan R" uniqKey="Weiss S" first="Susan R." last="Weiss">Susan R. Weiss</name><affiliation><nlm:aff id="af010">Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA</nlm:aff></affiliation></author><author><name sortKey="Silverman, Robert H" sort="Silverman, Robert H" uniqKey="Silverman R" first="Robert H." last="Silverman">Robert H. Silverman</name><affiliation><nlm:aff id="af005">Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmc">7129261</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7129261</idno><idno type="RBID">PMC:7129261</idno><idno type="doi">10.1016/j.cyto.2015.08.207</idno><idno type="pmid">NONE</idno><date when="2015">2015</date><idno type="wicri:Area/Pmc/Corpus">000575</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000575</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">ID: 203</title><author><name sortKey="Jha, Babal K" sort="Jha, Babal K" uniqKey="Jha B" first="Babal K." last="Jha">Babal K. Jha</name><affiliation><nlm:aff id="af005">Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA</nlm:aff></affiliation></author><author><name sortKey="Thornbrough, Joshua M" sort="Thornbrough, Joshua M" uniqKey="Thornbrough J" first="Joshua M." last="Thornbrough">Joshua M. Thornbrough</name><affiliation><nlm:aff id="af010">Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA</nlm:aff></affiliation></author><author><name sortKey="Goldstein, Stephen A" sort="Goldstein, Stephen A" uniqKey="Goldstein S" first="Stephen A." last="Goldstein">Stephen A. Goldstein</name><affiliation><nlm:aff id="af010">Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA</nlm:aff></affiliation></author><author><name sortKey="Elliott, Ruth" sort="Elliott, Ruth" uniqKey="Elliott R" first="Ruth" last="Elliott">Ruth Elliott</name><affiliation><nlm:aff id="af010">Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA</nlm:aff></affiliation></author><author><name sortKey="Weiss, Susan R" sort="Weiss, Susan R" uniqKey="Weiss S" first="Susan R." last="Weiss">Susan R. Weiss</name><affiliation><nlm:aff id="af010">Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA</nlm:aff></affiliation></author><author><name sortKey="Silverman, Robert H" sort="Silverman, Robert H" uniqKey="Silverman R" first="Robert H." last="Silverman">Robert H. Silverman</name><affiliation><nlm:aff id="af005">Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA</nlm:aff></affiliation></author></analytic><series><title level="j">Cytokine</title><idno type="ISSN">1043-4666</idno><idno type="eISSN">1096-0023</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Efficient and productive virus infection often requires viral countermeasures that block innate immunity. The interferon-inducible 2′,5′-oligoadenylate (2-5A) synthetases (OAS) and ribonuclease L (RNase L) are components of a potent host antiviral pathway. We previously showed that murine coronavirus (MHV) accessory protein ns2, group A rotavirus (RVA) VP3 carboxy-terminal domain (VP3-CTD), and mammalian AKAP7 are members of 2H phosphoesterase superfamily with 2′-phosphodiesterase (2′-PDE) activity that potently cleaves 2-5A thereby preventing activation of RNase L (Zhao, Jha et al., PMID: <ext-link ext-link-type="uri" xlink:href="pmid:22704621" id="ir005">22704621</ext-link>; Zhang, Jha et al., PMID: <ext-link ext-link-type="uri" xlink:href="pmid:23878220" id="ir010">23878220</ext-link> and Gusho, Zhang, Jha et al., PMID: <ext-link ext-link-type="uri" xlink:href="pmid:24987090" id="ir015">24987090</ext-link>). Here, we will demonstrate that Middle East respiratory syndrome (MERS)-CoV gene NS4b encodes a homologous and similar PDE that cleaves 2-5A in vitro (km/Kcat = 12.1 M<sup>−1</sup> s<sup>−1</sup>), inhibits 2-5A accumulation in cell culture and prevents ribosomal (r) RNA degradation in murine bone marrow macrophages (BMM), a hallmark of RNase L antagonism, and rescues an MHV mutant virus with a catalytically inactive NS2a protein unable to antagonize RNase L in vivo. Interestingly, NS4b has a nuclear localization signal however there is a mixed nuclear/cytoplasmic localization when overexpressed in human airway cell line A549 and in BMM when expressed from chimeric MHV. Viral evasion of OAS/RNase L pathway is a critical hepatovirulence determinant for lineage A Betacoronavirus mouse hepatitis virus (MHV). Taken together, our data suggest that RNase L antagonism may be a critical component of MERS-CoV pathogenesis. Additionally, this is the first evidence of RNase L antagonism by a lineage C Betacoronavirus.</p></div></front></TEI><pmc article-type="abstract"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Cytokine</journal-id><journal-id journal-id-type="iso-abbrev">Cytokine</journal-id><journal-title-group><journal-title>Cytokine</journal-title></journal-title-group><issn pub-type="ppub">1043-4666</issn><issn pub-type="epub">1096-0023</issn><publisher><publisher-name>Elsevier Science Ltd</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmc">7129261</article-id><article-id pub-id-type="publisher-id">S1043-4666(15)00473-1</article-id><article-id pub-id-type="doi">10.1016/j.cyto.2015.08.207</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>ID: 203</article-title><subtitle>Middle East respiratory syndrome coronavirus accessory protein NS4b is a 2H-Phosphoesterase that degrades 2′,5′-oligoadenylate activators of RNase L</subtitle></title-group><contrib-group><contrib contrib-type="author" id="au005"><name><surname>Jha</surname><given-names>Babal K.</given-names></name><xref rid="af005" ref-type="aff">1</xref><xref rid="cor1" ref-type="corresp">⁎</xref></contrib><contrib contrib-type="author" id="au010"><name><surname>Thornbrough</surname><given-names>Joshua M.</given-names></name><xref rid="af010" ref-type="aff">2</xref></contrib><contrib contrib-type="author" id="au015"><name><surname>Goldstein</surname><given-names>Stephen A.</given-names></name><xref rid="af010" ref-type="aff">2</xref></contrib><contrib contrib-type="author" id="au020"><name><surname>Elliott</surname><given-names>Ruth</given-names></name><xref rid="af010" ref-type="aff">2</xref></contrib><contrib contrib-type="author" id="au025"><name><surname>Weiss</surname><given-names>Susan R.</given-names></name><xref rid="af010" ref-type="aff">2</xref></contrib><contrib contrib-type="author" id="au030"><name><surname>Silverman</surname><given-names>Robert H.</given-names></name><xref rid="af005" ref-type="aff">1</xref></contrib></contrib-group><aff id="af005"><label>1</label>Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA</aff><aff id="af010"><label>2</label>Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA</aff><author-notes><corresp id="cor1"><label>⁎</label>Corresponding author.</corresp></author-notes><pub-date pub-type="pmc-release"><day>11</day><month>9</month><year>2015</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on .</pmc-comment>
<pub-date pub-type="ppub"><month>11</month><year>2015</year></pub-date><pub-date pub-type="epub"><day>11</day><month>9</month><year>2015</year></pub-date><volume>76</volume><issue>1</issue><fpage>101</fpage><lpage>101</lpage><permissions><copyright-year>2015</copyright-year></permissions><abstract id="ab005"><p>Efficient and productive virus infection often requires viral countermeasures that block innate immunity. The interferon-inducible 2′,5′-oligoadenylate (2-5A) synthetases (OAS) and ribonuclease L (RNase L) are components of a potent host antiviral pathway. We previously showed that murine coronavirus (MHV) accessory protein ns2, group A rotavirus (RVA) VP3 carboxy-terminal domain (VP3-CTD), and mammalian AKAP7 are members of 2H phosphoesterase superfamily with 2′-phosphodiesterase (2′-PDE) activity that potently cleaves 2-5A thereby preventing activation of RNase L (Zhao, Jha et al., PMID: <ext-link ext-link-type="uri" xlink:href="pmid:22704621" id="ir005">22704621</ext-link>; Zhang, Jha et al., PMID: <ext-link ext-link-type="uri" xlink:href="pmid:23878220" id="ir010">23878220</ext-link> and Gusho, Zhang, Jha et al., PMID: <ext-link ext-link-type="uri" xlink:href="pmid:24987090" id="ir015">24987090</ext-link>). Here, we will demonstrate that Middle East respiratory syndrome (MERS)-CoV gene NS4b encodes a homologous and similar PDE that cleaves 2-5A in vitro (km/Kcat = 12.1 M<sup>−1</sup> s<sup>−1</sup>), inhibits 2-5A accumulation in cell culture and prevents ribosomal (r) RNA degradation in murine bone marrow macrophages (BMM), a hallmark of RNase L antagonism, and rescues an MHV mutant virus with a catalytically inactive NS2a protein unable to antagonize RNase L in vivo. Interestingly, NS4b has a nuclear localization signal however there is a mixed nuclear/cytoplasmic localization when overexpressed in human airway cell line A549 and in BMM when expressed from chimeric MHV. Viral evasion of OAS/RNase L pathway is a critical hepatovirulence determinant for lineage A Betacoronavirus mouse hepatitis virus (MHV). Taken together, our data suggest that RNase L antagonism may be a critical component of MERS-CoV pathogenesis. Additionally, this is the first evidence of RNase L antagonism by a lineage C Betacoronavirus.</p></abstract></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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