A conserved region of nonstructural protein 1 from alphacoronaviruses inhibits host gene expression and is critical for viral virulence
Identifieur interne : 000B92 ( Main/Exploration ); précédent : 000B91; suivant : 000B93A conserved region of nonstructural protein 1 from alphacoronaviruses inhibits host gene expression and is critical for viral virulence
Auteurs : Zhou Shen [République populaire de Chine] ; Gang Wang [République populaire de Chine] ; Yiling Yang [République populaire de Chine] ; Jiale Shi [République populaire de Chine] ; Liurong Fang [République populaire de Chine] ; Fang Li [États-Unis] ; Shaobo Xiao [République populaire de Chine] ; Zhen F. Fu [République populaire de Chine, États-Unis] ; Guiqing Peng [République populaire de Chine]Source :
- The Journal of Biological Chemistry [ 0021-9258 ] ; 2019.
Abstract
Coronaviruses are enveloped, single-stranded RNA viruses that are distributed worldwide. They include transmissible gastroenteritis virus (TGEV), porcine epidemic diarrhea virus (PEDV), and the human coronaviruses severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), many of which seriously endanger human health and well-being. Only alphacoronaviruses and betacoronaviruses harbor nonstructural protein 1 (nsp1), which performs multiple functions in inhibiting antiviral host responses. The role of the C terminus of betacoronavirus nsp1 in virulence has been characterized, but the location of the alphacoronavirus nsp1 region that is important for virulence remains unclear. Here, using TGEV nsp1 as a model to explore the function of this protein in alphacoronaviruses, we demonstrate that alphacoronavirus nsp1 inhibits host gene expression. Solving the crystal structure of full-length TGEV at 1.85-Å resolution and conducting several biochemical analyses, we observed that a specific motif (amino acids 91–95) of alphacoronavirus nsp1 is a conserved region that inhibits host protein synthesis. Using a reverse-genetics system based on CRISPR/Cas9 technology to construct a recombinant TGEV in which this specific nsp1 motif was altered, we found that this mutation does not affect virus replication in cell culture but significantly reduces TGEV pathogenicity in pigs. Taken together, our findings suggest that alphacoronavirus nsp1 is an essential virulence determinant, providing a potential paradigm for the development of a new attenuated vaccine based on modified nsp1.
Url:
DOI: 10.1074/jbc.RA119.009713
PubMed: 31350335
PubMed Central: 6746460
Affiliations:
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Chine</country><wicri:regionArea>College of Life Science and Technology, Huazhong Agricultural University, Wuhan 430070</wicri:regionArea><placeName><settlement type="city">Wuhan</settlement><region type="région">Hubei</region></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31350335</idno><idno type="pmc">6746460</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746460</idno><idno type="RBID">PMC:6746460</idno><idno type="doi">10.1074/jbc.RA119.009713</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">001110</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001110</idno><idno type="wicri:Area/Pmc/Curation">001110</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">001110</idno><idno type="wicri:Area/Pmc/Checkpoint">000496</idno><idno type="wicri:explorRef" wicri:stream="Pmc" 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xml:lang="en" level="a" type="main">A conserved region of nonstructural protein 1 from alphacoronaviruses
inhibits host gene expression and is critical for viral
virulence</title><author><name sortKey="Shen, Zhou" sort="Shen, Zhou" uniqKey="Shen Z" first="Zhou" last="Shen">Zhou Shen</name><affiliation wicri:level="1"><nlm:aff id="aff1">State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070</wicri:regionArea><placeName><settlement type="city">Wuhan</settlement><region type="région">Hubei</region></placeName></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2">Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070</wicri:regionArea><placeName><settlement type="city">Wuhan</settlement><region type="région">Hubei</region></placeName></affiliation></author><author><name sortKey="Wang, Gang" sort="Wang, Gang" uniqKey="Wang G" first="Gang" last="Wang">Gang Wang</name><affiliation wicri:level="1"><nlm:aff id="aff1">State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070</wicri:regionArea><placeName><settlement type="city">Wuhan</settlement><region type="région">Hubei</region></placeName></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2">Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070</wicri:regionArea><placeName><settlement type="city">Wuhan</settlement><region type="région">Hubei</region></placeName></affiliation></author><author><name sortKey="Yang, Yiling" sort="Yang, Yiling" uniqKey="Yang Y" first="Yiling" last="Yang">Yiling Yang</name><affiliation wicri:level="1"><nlm:aff id="aff1">State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070</wicri:regionArea><placeName><settlement type="city">Wuhan</settlement><region type="région">Hubei</region></placeName></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2">Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070</wicri:regionArea><placeName><settlement type="city">Wuhan</settlement><region type="région">Hubei</region></placeName></affiliation></author><author><name sortKey="Shi, Jiale" sort="Shi, Jiale" uniqKey="Shi J" first="Jiale" last="Shi">Jiale Shi</name><affiliation wicri:level="1"><nlm:aff id="aff1">State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070</wicri:regionArea><placeName><settlement type="city">Wuhan</settlement><region type="région">Hubei</region></placeName></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2">Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070</wicri:regionArea><placeName><settlement type="city">Wuhan</settlement><region type="région">Hubei</region></placeName></affiliation></author><author><name sortKey="Fang, Liurong" sort="Fang, Liurong" uniqKey="Fang L" first="Liurong" last="Fang">Liurong Fang</name><affiliation wicri:level="1"><nlm:aff id="aff1">State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070</wicri:regionArea><placeName><settlement type="city">Wuhan</settlement><region type="région">Hubei</region></placeName></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2">Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070</wicri:regionArea><placeName><settlement type="city">Wuhan</settlement><region type="région">Hubei</region></placeName></affiliation></author><author><name sortKey="Li, Fang" sort="Li, Fang" uniqKey="Li F" first="Fang" last="Li">Fang Li</name><affiliation wicri:level="2"><nlm:aff id="aff3">Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, Minnesota 55108</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Minnesota</region></placeName><wicri:cityArea>Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul</wicri:cityArea></affiliation></author><author><name sortKey="Xiao, Shaobo" sort="Xiao, Shaobo" uniqKey="Xiao S" first="Shaobo" last="Xiao">Shaobo Xiao</name><affiliation wicri:level="1"><nlm:aff id="aff1">State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070</wicri:regionArea><placeName><settlement type="city">Wuhan</settlement><region type="région">Hubei</region></placeName></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2">Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070</wicri:regionArea><placeName><settlement type="city">Wuhan</settlement><region type="région">Hubei</region></placeName></affiliation></author><author><name sortKey="Fu, Zhen F" sort="Fu, Zhen F" uniqKey="Fu Z" first="Zhen F." last="Fu">Zhen F. Fu</name><affiliation wicri:level="1"><nlm:aff id="aff1">State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070</wicri:regionArea><placeName><settlement type="city">Wuhan</settlement><region type="région">Hubei</region></placeName></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2">Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070</wicri:regionArea><placeName><settlement type="city">Wuhan</settlement><region type="région">Hubei</region></placeName></affiliation><affiliation wicri:level="2"><nlm:aff id="aff4">Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, Georgia 30602</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Géorgie (États-Unis)</region></placeName><wicri:cityArea>Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens</wicri:cityArea></affiliation></author><author><name sortKey="Peng, Guiqing" sort="Peng, Guiqing" uniqKey="Peng G" first="Guiqing" last="Peng">Guiqing Peng</name><affiliation wicri:level="1"><nlm:aff id="aff1">State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070</wicri:regionArea><placeName><settlement type="city">Wuhan</settlement><region type="région">Hubei</region></placeName></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2">Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070</wicri:regionArea><placeName><settlement type="city">Wuhan</settlement><region type="région">Hubei</region></placeName></affiliation><affiliation wicri:level="1"><nlm:aff id="aff5">College of Life Science and Technology, Huazhong Agricultural University, Wuhan 430070, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>College of Life Science and Technology, Huazhong Agricultural University, Wuhan 430070</wicri:regionArea><placeName><settlement type="city">Wuhan</settlement><region type="région">Hubei</region></placeName></affiliation></author></analytic><series><title level="j">The Journal of Biological Chemistry</title><idno type="ISSN">0021-9258</idno><idno type="eISSN">1083-351X</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Coronaviruses are enveloped, single-stranded RNA viruses that are distributed
worldwide. They include transmissible gastroenteritis virus (TGEV), porcine
epidemic diarrhea virus (PEDV), and the human coronaviruses severe acute
respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome
coronavirus (MERS-CoV), many of which seriously endanger human health and
well-being. Only alphacoronaviruses and betacoronaviruses harbor nonstructural
protein 1 (nsp1), which performs multiple functions in inhibiting antiviral host
responses. The role of the C terminus of betacoronavirus nsp1 in virulence has
been characterized, but the location of the alphacoronavirus nsp1 region that is
important for virulence remains unclear. Here, using TGEV nsp1 as a model to
explore the function of this protein in alphacoronaviruses, we demonstrate that
alphacoronavirus nsp1 inhibits host gene expression. Solving the crystal
structure of full-length TGEV at 1.85-Å resolution and conducting several
biochemical analyses, we observed that a specific motif (amino acids
91–95) of alphacoronavirus nsp1 is a conserved region that inhibits host
protein synthesis. Using a reverse-genetics system based on CRISPR/Cas9
technology to construct a recombinant TGEV in which this specific nsp1 motif was
altered, we found that this mutation does not affect virus replication in cell
culture but significantly reduces TGEV pathogenicity in pigs. Taken together,
our findings suggest that alphacoronavirus nsp1 is an essential virulence
determinant, providing a potential paradigm for the development of a new
attenuated vaccine based on modified nsp1.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Weiss, S X0a R" uniqKey="Weiss S">S.
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