ID: 203
Identifieur interne : 000E35 ( Pmc/Checkpoint ); précédent : 000E34; suivant : 000E36ID: 203
Auteurs : Babal K. Jha [États-Unis] ; Joshua M. Thornbrough [États-Unis] ; Stephen A. Goldstein [États-Unis] ; Ruth Elliott [États-Unis] ; Susan R. Weiss [États-Unis] ; Robert H. Silverman [États-Unis]Source :
- Cytokine [ 1043-4666 ] ; 2015.
Abstract
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:
Url:
DOI: 10.1016/j.cyto.2015.08.207
PubMed: NONE
PubMed Central: 7129261
Affiliations:
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PMC:7129261Le document en format XML
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<author><name sortKey="Thornbrough, Joshua M" sort="Thornbrough, Joshua M" uniqKey="Thornbrough J" first="Joshua M." last="Thornbrough">Joshua M. Thornbrough</name>
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<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>
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<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>
<affiliations><list><country><li>États-Unis</li>
</country>
<region><li>Ohio</li>
<li>Pennsylvanie</li>
</region>
</list>
<tree><country name="États-Unis"><region name="Ohio"><name sortKey="Jha, Babal K" sort="Jha, Babal K" uniqKey="Jha B" first="Babal K." last="Jha">Babal K. Jha</name>
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<name sortKey="Elliott, Ruth" sort="Elliott, Ruth" uniqKey="Elliott R" first="Ruth" last="Elliott">Ruth Elliott</name>
<name sortKey="Goldstein, Stephen A" sort="Goldstein, Stephen A" uniqKey="Goldstein S" first="Stephen A." last="Goldstein">Stephen A. Goldstein</name>
<name sortKey="Silverman, Robert H" sort="Silverman, Robert H" uniqKey="Silverman R" first="Robert H." last="Silverman">Robert H. Silverman</name>
<name sortKey="Thornbrough, Joshua M" sort="Thornbrough, Joshua M" uniqKey="Thornbrough J" first="Joshua M." last="Thornbrough">Joshua M. Thornbrough</name>
<name sortKey="Weiss, Susan R" sort="Weiss, Susan R" uniqKey="Weiss S" first="Susan R." last="Weiss">Susan R. Weiss</name>
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