Coronavirus nsp10/nsp16 Methyltransferase Can Be Targeted by nsp10-Derived Peptide In Vitro and In Vivo To Reduce Replication and Pathogenesis.
Identifieur interne : 000E13 ( PubMed/Curation ); précédent : 000E12; suivant : 000E14Coronavirus nsp10/nsp16 Methyltransferase Can Be Targeted by nsp10-Derived Peptide In Vitro and In Vivo To Reduce Replication and Pathogenesis.
Auteurs : Yi Wang [République populaire de Chine] ; Ying Sun [République populaire de Chine] ; Andong Wu [République populaire de Chine] ; Shan Xu [République populaire de Chine] ; Ruangang Pan [République populaire de Chine] ; Cong Zeng [République populaire de Chine] ; Xu Jin [République populaire de Chine] ; Xingyi Ge [République populaire de Chine] ; Zhengli Shi [République populaire de Chine] ; Tero Ahola [Finlande] ; Yu Chen [République populaire de Chine] ; Deyin Guo [République populaire de Chine]Source :
- Journal of virology [ 1098-5514 ] ; 2015.
Descripteurs français
- KwdFr :
- Alanine transaminase (métabolisme), Animaux, Humains, Lignée cellulaire, Luciferases, Methyltransferases (métabolisme), Peptides (génétique), Peptides (pharmacologie), Protéines virales non structurales (métabolisme), Rats, Réplication virale (), Souris, Virus de l'hépatite murine (génétique), Virus de l'hépatite murine (pathogénicité), Virus du SRAS (enzymologie).
- MESH :
- enzymologie : Virus du SRAS.
- génétique : Peptides, Virus de l'hépatite murine.
- métabolisme : Alanine transaminase, Methyltransferases, Protéines virales non structurales.
- pathogénicité : Virus de l'hépatite murine.
- pharmacologie : Peptides.
- Animaux, Humains, Lignée cellulaire, Luciferases, Rats, Réplication virale, Souris.
English descriptors
- KwdEn :
- Alanine Transaminase (metabolism), Animals, Cell Line, Humans, Luciferases, Methyltransferases (metabolism), Mice, Murine hepatitis virus (genetics), Murine hepatitis virus (pathogenicity), Peptides (genetics), Peptides (pharmacology), Rats, SARS Virus (enzymology), Viral Nonstructural Proteins (metabolism), Virus Replication (drug effects).
- MESH :
- chemical , genetics : Peptides.
- chemical , metabolism : Alanine Transaminase, Methyltransferases, Viral Nonstructural Proteins.
- drug effects : Virus Replication.
- enzymology : SARS Virus.
- genetics : Murine hepatitis virus.
- pathogenicity : Murine hepatitis virus.
- chemical , pharmacology : Peptides.
- Animals, Cell Line, Humans, Luciferases, Mice, Rats.
Abstract
The 5' cap structures of eukaryotic mRNAs are important for RNA stability and protein translation. Many viruses that replicate in the cytoplasm of eukaryotes have evolved 2'-O-methyltransferases (2'-O-MTase) to autonomously modify their mRNAs and carry a cap-1 structure (m7GpppNm) at the 5' end, thereby facilitating viral replication and escaping innate immune recognition in host cells. Previous studies showed that the 2'-O-MTase activity of severe acute respiratory syndrome coronavirus (SARS-CoV) nonstructural protein 16 (nsp16) needs to be activated by nsp10, whereas nsp16 of feline coronavirus (FCoV) alone possesses 2'-O-MTase activity (E. Decroly et al., J Virol 82:8071-8084, 2008, http://dx.doi.org/10.1128/JVI.00407-08; M. Bouvet et al., PLoS Pathog 6:e1000863, 2010, http://dx.doi.org/10.1371/journal.ppat.1000863; E. Decroly et al., PLoS Pathog 7:e1002059, 2011, http://dx.doi.org/10.1371/journal.ppat.1002059; Y. Chen et al., PLoS Pathog 7:e1002294, 2011, http://dx.doi.org/10.1371/journal.ppat.1002294) . In this study, we demonstrate that stimulation of nsp16 2'-O-MTase activity by nsp10 is a universal and conserved mechanism in coronaviruses, including FCoV, and that nsp10 is functionally interchangeable in the stimulation of nsp16 of different coronaviruses. Based on our current and previous studies, we designed a peptide (TP29) from the sequence of the interaction interface of mouse hepatitis virus (MHV) nsp10 and demonstrated that the peptide inhibits the 2'-O-MTase activity of different coronaviruses in biochemical assays and the viral replication in MHV infection and SARS-CoV replicon models. Interestingly, the peptide TP29 exerted robust inhibitory effects in vivo in MHV-infected mice by impairing MHV virulence and pathogenesis through suppressing virus replication and enhancing type I interferon production at an early stage of infection. Therefore, as a proof of principle, the current results indicate that coronavirus 2'-O-MTase activity can be targeted in vitro and in vivo.
DOI: 10.1128/JVI.00948-15
PubMed: 26041293
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<front><div type="abstract" xml:lang="en">The 5' cap structures of eukaryotic mRNAs are important for RNA stability and protein translation. Many viruses that replicate in the cytoplasm of eukaryotes have evolved 2'-O-methyltransferases (2'-O-MTase) to autonomously modify their mRNAs and carry a cap-1 structure (m7GpppNm) at the 5' end, thereby facilitating viral replication and escaping innate immune recognition in host cells. Previous studies showed that the 2'-O-MTase activity of severe acute respiratory syndrome coronavirus (SARS-CoV) nonstructural protein 16 (nsp16) needs to be activated by nsp10, whereas nsp16 of feline coronavirus (FCoV) alone possesses 2'-O-MTase activity (E. Decroly et al., J Virol 82:8071-8084, 2008, http://dx.doi.org/10.1128/JVI.00407-08; M. Bouvet et al., PLoS Pathog 6:e1000863, 2010, http://dx.doi.org/10.1371/journal.ppat.1000863; E. Decroly et al., PLoS Pathog 7:e1002059, 2011, http://dx.doi.org/10.1371/journal.ppat.1002059; Y. Chen et al., PLoS Pathog 7:e1002294, 2011, http://dx.doi.org/10.1371/journal.ppat.1002294) . In this study, we demonstrate that stimulation of nsp16 2'-O-MTase activity by nsp10 is a universal and conserved mechanism in coronaviruses, including FCoV, and that nsp10 is functionally interchangeable in the stimulation of nsp16 of different coronaviruses. Based on our current and previous studies, we designed a peptide (TP29) from the sequence of the interaction interface of mouse hepatitis virus (MHV) nsp10 and demonstrated that the peptide inhibits the 2'-O-MTase activity of different coronaviruses in biochemical assays and the viral replication in MHV infection and SARS-CoV replicon models. Interestingly, the peptide TP29 exerted robust inhibitory effects in vivo in MHV-infected mice by impairing MHV virulence and pathogenesis through suppressing virus replication and enhancing type I interferon production at an early stage of infection. Therefore, as a proof of principle, the current results indicate that coronavirus 2'-O-MTase activity can be targeted in vitro and in vivo.</div>
</front>
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<Abstract><AbstractText Label="UNLABELLED">The 5' cap structures of eukaryotic mRNAs are important for RNA stability and protein translation. Many viruses that replicate in the cytoplasm of eukaryotes have evolved 2'-O-methyltransferases (2'-O-MTase) to autonomously modify their mRNAs and carry a cap-1 structure (m7GpppNm) at the 5' end, thereby facilitating viral replication and escaping innate immune recognition in host cells. Previous studies showed that the 2'-O-MTase activity of severe acute respiratory syndrome coronavirus (SARS-CoV) nonstructural protein 16 (nsp16) needs to be activated by nsp10, whereas nsp16 of feline coronavirus (FCoV) alone possesses 2'-O-MTase activity (E. Decroly et al., J Virol 82:8071-8084, 2008, http://dx.doi.org/10.1128/JVI.00407-08; M. Bouvet et al., PLoS Pathog 6:e1000863, 2010, http://dx.doi.org/10.1371/journal.ppat.1000863; E. Decroly et al., PLoS Pathog 7:e1002059, 2011, http://dx.doi.org/10.1371/journal.ppat.1002059; Y. Chen et al., PLoS Pathog 7:e1002294, 2011, http://dx.doi.org/10.1371/journal.ppat.1002294) . In this study, we demonstrate that stimulation of nsp16 2'-O-MTase activity by nsp10 is a universal and conserved mechanism in coronaviruses, including FCoV, and that nsp10 is functionally interchangeable in the stimulation of nsp16 of different coronaviruses. Based on our current and previous studies, we designed a peptide (TP29) from the sequence of the interaction interface of mouse hepatitis virus (MHV) nsp10 and demonstrated that the peptide inhibits the 2'-O-MTase activity of different coronaviruses in biochemical assays and the viral replication in MHV infection and SARS-CoV replicon models. Interestingly, the peptide TP29 exerted robust inhibitory effects in vivo in MHV-infected mice by impairing MHV virulence and pathogenesis through suppressing virus replication and enhancing type I interferon production at an early stage of infection. Therefore, as a proof of principle, the current results indicate that coronavirus 2'-O-MTase activity can be targeted in vitro and in vivo.</AbstractText>
<AbstractText Label="IMPORTANCE" NlmCategory="OBJECTIVE">Coronaviruses are important pathogens of animals and human with high zoonotic potential. SARS-CoV encodes the 2'-O-MTase that is composed of the catalytic subunit nsp16 and the stimulatory subunit nsp10 and plays an important role in virus genome replication and evasion from innate immunity. Our current results demonstrate that stimulation of nsp16 2'-O-MTase activity by nsp10 is a common mechanism for coronaviruses, and nsp10 is functionally interchangeable in the stimulation of nsp16 among different coronaviruses, which underlies the rationale for developing inhibitory peptides. We demonstrate that a peptide derived from the nsp16-interacting domain of MHV nsp10 could inhibit 2'-O-MTase activity of different coronaviruses in vitro and viral replication of MHV and SARS-CoV replicon in cell culture, and it could strongly inhibit virus replication and pathogenesis in MHV-infected mice. This work makes it possible to develop broad-spectrum peptide inhibitors by targeting the nsp16/nsp10 2'-O-MTase of coronaviruses.</AbstractText>
<CopyrightInformation>Copyright © 2015, American Society for Microbiology. All Rights Reserved.</CopyrightInformation>
</Abstract>
<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Wang</LastName>
<ForeName>Yi</ForeName>
<Initials>Y</Initials>
<AffiliationInfo><Affiliation>State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Sun</LastName>
<ForeName>Ying</ForeName>
<Initials>Y</Initials>
<AffiliationInfo><Affiliation>Department of Pathogen Biology, Henan University of TCM, Zhengzhou, China.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Wu</LastName>
<ForeName>Andong</ForeName>
<Initials>A</Initials>
<AffiliationInfo><Affiliation>State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Xu</LastName>
<ForeName>Shan</ForeName>
<Initials>S</Initials>
<AffiliationInfo><Affiliation>State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Pan</LastName>
<ForeName>Ruangang</ForeName>
<Initials>R</Initials>
<AffiliationInfo><Affiliation>State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Zeng</LastName>
<ForeName>Cong</ForeName>
<Initials>C</Initials>
<AffiliationInfo><Affiliation>State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Jin</LastName>
<ForeName>Xu</ForeName>
<Initials>X</Initials>
<AffiliationInfo><Affiliation>State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Ge</LastName>
<ForeName>Xingyi</ForeName>
<Initials>X</Initials>
<AffiliationInfo><Affiliation>Center for Emerging Infectious Diseases, State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Shi</LastName>
<ForeName>Zhengli</ForeName>
<Initials>Z</Initials>
<AffiliationInfo><Affiliation>Center for Emerging Infectious Diseases, State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Ahola</LastName>
<ForeName>Tero</ForeName>
<Initials>T</Initials>
<AffiliationInfo><Affiliation>Department of Food and Environmental Sciences, University of Helsinki, Helsinki, Finland.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Chen</LastName>
<ForeName>Yu</ForeName>
<Initials>Y</Initials>
<AffiliationInfo><Affiliation>State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China chenyu@whu.edu.cn dguo@whu.edu.cn.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Guo</LastName>
<ForeName>Deyin</ForeName>
<Initials>D</Initials>
<AffiliationInfo><Affiliation>State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China chenyu@whu.edu.cn dguo@whu.edu.cn.</Affiliation>
</AffiliationInfo>
</Author>
</AuthorList>
<Language>eng</Language>
<PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType>
<PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType>
</PublicationTypeList>
<ArticleDate DateType="Electronic"><Year>2015</Year>
<Month>06</Month>
<Day>03</Day>
</ArticleDate>
</Article>
<MedlineJournalInfo><Country>United States</Country>
<MedlineTA>J Virol</MedlineTA>
<NlmUniqueID>0113724</NlmUniqueID>
<ISSNLinking>0022-538X</ISSNLinking>
</MedlineJournalInfo>
<ChemicalList><Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="C558878">Nsp10 protein, SARS virus</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D010455">Peptides</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D017361">Viral Nonstructural Proteins</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>EC 1.13.12.-</RegistryNumber>
<NameOfSubstance UI="D008156">Luciferases</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>EC 2.1.1.-</RegistryNumber>
<NameOfSubstance UI="D008780">Methyltransferases</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>EC 2.1.1.-</RegistryNumber>
<NameOfSubstance UI="C558879">Nsp16 protein, SARS virus</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>EC 2.6.1.2</RegistryNumber>
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<CitationSubset>IM</CitationSubset>
<MeshHeadingList><MeshHeading><DescriptorName UI="D000410" MajorTopicYN="N">Alanine Transaminase</DescriptorName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D002460" MajorTopicYN="N">Cell Line</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D008156" MajorTopicYN="N">Luciferases</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D008780" MajorTopicYN="N">Methyltransferases</DescriptorName>
<QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D051379" MajorTopicYN="N">Mice</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D006517" MajorTopicYN="N">Murine hepatitis virus</DescriptorName>
<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
<QualifierName UI="Q000472" MajorTopicYN="Y">pathogenicity</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D010455" MajorTopicYN="N">Peptides</DescriptorName>
<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
<QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D051381" MajorTopicYN="N">Rats</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D045473" MajorTopicYN="N">SARS Virus</DescriptorName>
<QualifierName UI="Q000201" MajorTopicYN="Y">enzymology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D017361" MajorTopicYN="N">Viral Nonstructural Proteins</DescriptorName>
<QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D014779" MajorTopicYN="N">Virus Replication</DescriptorName>
<QualifierName UI="Q000187" MajorTopicYN="Y">drug effects</QualifierName>
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