Lineage A Betacoronavirus NS2 Proteins and the Homologous Torovirus Berne pp1a Carboxy-Terminal Domain Are Phosphodiesterases That Antagonize Activation of RNase L.
Identifieur interne : 000E12 ( Main/Exploration ); précédent : 000E11; suivant : 000E13Lineage A Betacoronavirus NS2 Proteins and the Homologous Torovirus Berne pp1a Carboxy-Terminal Domain Are Phosphodiesterases That Antagonize Activation of RNase L.
Auteurs : Stephen A. Goldstein [États-Unis] ; Joshua M. Thornbrough [États-Unis] ; Rong Zhang [États-Unis] ; Babal K. Jha [États-Unis] ; Yize Li [États-Unis] ; Ruth Elliott [États-Unis] ; Katherine Quiroz-Figueroa [États-Unis] ; Annie I. Chen [États-Unis] ; Robert H. Silverman [États-Unis] ; Susan R. Weiss [États-Unis]Source :
- Journal of virology [ 1098-5514 ] ; 2017.
Descripteurs français
- KwdFr :
- Activation enzymatique, Animaux, Coronavirus du syndrome respiratoire du Moyen-Orient (enzymologie), Cricetinae, Domaine catalytique, Endoribonucleases (métabolisme), Lignée cellulaire, Macrophages (virologie), Nucléotides adényliques (), Oligoribonucléotides (), Phosphodiesterases (), Phosphodiesterases (physiologie), Protéines virales non structurales (), Protéines virales non structurales (physiologie), Réplication virale, Souris, Souris de lignée C57BL, Souris knockout, Séquence conservée, Séquence d'acides aminés, Torovirus (enzymologie), Virus de l'hépatite murine (enzymologie).
- MESH :
- enzymologie : Coronavirus du syndrome respiratoire du Moyen-Orient, Torovirus, Virus de l'hépatite murine.
- métabolisme : Endoribonucleases.
- physiologie : Phosphodiesterases, Protéines virales non structurales.
- virologie : Macrophages.
- Activation enzymatique, Animaux, Cricetinae, Domaine catalytique, Lignée cellulaire, Nucléotides adényliques, Oligoribonucléotides, Phosphodiesterases, Protéines virales non structurales, Réplication virale, Souris, Souris de lignée C57BL, Souris knockout, Séquence conservée, Séquence d'acides aminés.
English descriptors
- KwdEn :
- Adenine Nucleotides (chemistry), Amino Acid Sequence, Animals, Catalytic Domain, Cell Line, Conserved Sequence, Cricetinae, Endoribonucleases (metabolism), Enzyme Activation, Macrophages (virology), Mice, Mice, Inbred C57BL, Mice, Knockout, Middle East Respiratory Syndrome Coronavirus (enzymology), Murine hepatitis virus (enzymology), Oligoribonucleotides (chemistry), Phosphoric Diester Hydrolases (chemistry), Phosphoric Diester Hydrolases (physiology), Torovirus (enzymology), Viral Nonstructural Proteins (chemistry), Viral Nonstructural Proteins (physiology), Virus Replication.
- MESH :
- chemical , chemistry : Adenine Nucleotides, Oligoribonucleotides, Phosphoric Diester Hydrolases, Viral Nonstructural Proteins.
- chemical , metabolism : Endoribonucleases.
- enzymology : Middle East Respiratory Syndrome Coronavirus, Murine hepatitis virus, Torovirus.
- chemical , physiology : Phosphoric Diester Hydrolases, Viral Nonstructural Proteins.
- virology : Macrophages.
- Amino Acid Sequence, Animals, Catalytic Domain, Cell Line, Conserved Sequence, Cricetinae, Enzyme Activation, Mice, Mice, Inbred C57BL, Mice, Knockout, Virus Replication.
Abstract
Viruses in the family Coronaviridae, within the order Nidovirales, are etiologic agents of a range of human and animal diseases, including both mild and severe respiratory diseases in humans. These viruses encode conserved replicase and structural proteins as well as more diverse accessory proteins, encoded in the 3' ends of their genomes, that often act as host cell antagonists. We previously showed that 2',5'-phosphodiesterases (2',5'-PDEs) encoded by the prototypical Betacoronavirus, mouse hepatitis virus (MHV), and by Middle East respiratory syndrome-associated coronavirus antagonize the oligoadenylate-RNase L (OAS-RNase L) pathway. Here we report that additional coronavirus superfamily members, including lineage A betacoronaviruses and toroviruses infecting both humans and animals, encode 2',5'-PDEs capable of antagonizing RNase L. We used a chimeric MHV system (MHVMut) in which exogenous PDEs were expressed from an MHV backbone lacking the gene for a functional NS2 protein, the endogenous RNase L antagonist. With this system, we found that 2',5'-PDEs encoded by the human coronavirus HCoV-OC43 (OC43; an agent of the common cold), human enteric coronavirus (HECoV), equine coronavirus (ECoV), and equine torovirus Berne (BEV) are enzymatically active, rescue replication of MHVMut in bone marrow-derived macrophages, and inhibit RNase L-mediated rRNA degradation in these cells. Additionally, PDEs encoded by OC43 and BEV rescue MHVMut replication and restore pathogenesis in wild-type (WT) B6 mice. This finding expands the range of viruses known to encode antagonists of the potent OAS-RNase L antiviral pathway, highlighting its importance in a range of species as well as the selective pressures exerted on viruses to antagonize it.IMPORTANCE Viruses in the family Coronaviridae include important human and animal pathogens, including the recently emerged viruses severe acute respiratory syndrome-associated coronavirus (SARS-CoV) and Middle East respiratory syndrome-associated coronavirus (MERS-CoV). We showed previously that two viruses within the genus Betacoronavirus, mouse hepatitis virus (MHV) and MERS-CoV, encode 2',5'-phosphodiesterases (2',5'-PDEs) that antagonize the OAS-RNase L pathway, and we report here that these proteins are furthermore conserved among additional coronavirus superfamily members, including lineage A betacoronaviruses and toroviruses, suggesting that they may play critical roles in pathogenesis. As there are no licensed vaccines or effective antivirals against human coronaviruses and few against those infecting animals, identifying viral proteins contributing to virulence can inform therapeutic development. Thus, this work demonstrates that a potent antagonist of host antiviral defenses is encoded by multiple and diverse viruses within the family Coronaviridae, presenting a possible broad-spectrum therapeutic target.
DOI: 10.1128/JVI.02201-16
PubMed: 28003490
Affiliations:
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<term>Cell Line</term>
<term>Conserved Sequence</term>
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<term>Murine hepatitis virus (enzymology)</term>
<term>Oligoribonucleotides (chemistry)</term>
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<term>Animaux</term>
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<term>Domaine catalytique</term>
<term>Endoribonucleases (métabolisme)</term>
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<term>Mice</term>
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<term>Domaine catalytique</term>
<term>Lignée cellulaire</term>
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<front><div type="abstract" xml:lang="en">Viruses in the family <i>Coronaviridae</i>
, within the order <i>Nidovirales</i>
, are etiologic agents of a range of human and animal diseases, including both mild and severe respiratory diseases in humans. These viruses encode conserved replicase and structural proteins as well as more diverse accessory proteins, encoded in the 3' ends of their genomes, that often act as host cell antagonists. We previously showed that 2',5'-phosphodiesterases (2',5'-PDEs) encoded by the prototypical <i>Betacoronavirus</i>
, mouse hepatitis virus (MHV), and by Middle East respiratory syndrome-associated coronavirus antagonize the oligoadenylate-RNase L (OAS-RNase L) pathway. Here we report that additional coronavirus superfamily members, including lineage A betacoronaviruses and toroviruses infecting both humans and animals, encode 2',5'-PDEs capable of antagonizing RNase L. We used a chimeric MHV system (MHV<sup>Mut</sup>
) in which exogenous PDEs were expressed from an MHV backbone lacking the gene for a functional NS2 protein, the endogenous RNase L antagonist. With this system, we found that 2',5'-PDEs encoded by the human coronavirus HCoV-OC43 (OC43; an agent of the common cold), human enteric coronavirus (HECoV), equine coronavirus (ECoV), and equine torovirus Berne (BEV) are enzymatically active, rescue replication of MHV<sup>Mut</sup>
in bone marrow-derived macrophages, and inhibit RNase L-mediated rRNA degradation in these cells. Additionally, PDEs encoded by OC43 and BEV rescue MHV<sup>Mut</sup>
replication and restore pathogenesis in wild-type (WT) B6 mice. This finding expands the range of viruses known to encode antagonists of the potent OAS-RNase L antiviral pathway, highlighting its importance in a range of species as well as the selective pressures exerted on viruses to antagonize it.<b>IMPORTANCE</b>
Viruses in the family <i>Coronaviridae</i>
include important human and animal pathogens, including the recently emerged viruses severe acute respiratory syndrome-associated coronavirus (SARS-CoV) and Middle East respiratory syndrome-associated coronavirus (MERS-CoV). We showed previously that two viruses within the genus <i>Betacoronavirus</i>
, mouse hepatitis virus (MHV) and MERS-CoV, encode 2',5'-phosphodiesterases (2',5'-PDEs) that antagonize the OAS-RNase L pathway, and we report here that these proteins are furthermore conserved among additional coronavirus superfamily members, including lineage A betacoronaviruses and toroviruses, suggesting that they may play critical roles in pathogenesis. As there are no licensed vaccines or effective antivirals against human coronaviruses and few against those infecting animals, identifying viral proteins contributing to virulence can inform therapeutic development. Thus, this work demonstrates that a potent antagonist of host antiviral defenses is encoded by multiple and diverse viruses within the family <i>Coronaviridae</i>
, presenting a possible broad-spectrum therapeutic target.</div>
</front>
</TEI>
<affiliations><list><country><li>États-Unis</li>
</country>
<region><li>Ohio</li>
<li>Pennsylvanie</li>
</region>
</list>
<tree><country name="États-Unis"><region name="Pennsylvanie"><name sortKey="Goldstein, Stephen A" sort="Goldstein, Stephen A" uniqKey="Goldstein S" first="Stephen A" last="Goldstein">Stephen A. Goldstein</name>
</region>
<name sortKey="Chen, Annie I" sort="Chen, Annie I" uniqKey="Chen A" first="Annie I" last="Chen">Annie I. Chen</name>
<name sortKey="Elliott, Ruth" sort="Elliott, Ruth" uniqKey="Elliott R" first="Ruth" last="Elliott">Ruth Elliott</name>
<name sortKey="Jha, Babal K" sort="Jha, Babal K" uniqKey="Jha B" first="Babal K" last="Jha">Babal K. Jha</name>
<name sortKey="Li, Yize" sort="Li, Yize" uniqKey="Li Y" first="Yize" last="Li">Yize Li</name>
<name sortKey="Quiroz Figueroa, Katherine" sort="Quiroz Figueroa, Katherine" uniqKey="Quiroz Figueroa K" first="Katherine" last="Quiroz-Figueroa">Katherine Quiroz-Figueroa</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>
<name sortKey="Zhang, Rong" sort="Zhang, Rong" uniqKey="Zhang R" first="Rong" last="Zhang">Rong Zhang</name>
</country>
</tree>
</affiliations>
</record>
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