Host cell entry of Middle East respiratory syndrome coronavirus after two-step, furin-mediated activation of the spike protein.
Identifieur interne : 001C39 ( Main/Exploration ); précédent : 001C38; suivant : 001C40Host cell entry of Middle East respiratory syndrome coronavirus after two-step, furin-mediated activation of the spike protein.
Auteurs : Jean Kaoru Millet [États-Unis] ; Gary R. Whittaker [États-Unis]Source :
- Proceedings of the National Academy of Sciences of the United States of America [ 1091-6490 ] ; 2014.
Descripteurs français
- KwdFr :
- Animaux, Biologie informatique, Cellules HEK293, Cellules Vero, Coronavirus du syndrome respiratoire du Moyen-Orient (physiologie), Extinction de l'expression des gènes, Facteurs temps, Furine (), Glycoprotéine de spicule des coronavirus (métabolisme), Humains, Lignée cellulaire tumorale, Mutation, Peptide hydrolases (métabolisme), Petit ARN interférent (métabolisme), Prédisposition génétique à une maladie, Pénétration virale, Récepteurs viraux (métabolisme).
- MESH :
- métabolisme : Glycoprotéine de spicule des coronavirus, Peptide hydrolases, Petit ARN interférent, Récepteurs viraux.
- physiologie : Coronavirus du syndrome respiratoire du Moyen-Orient.
- Animaux, Biologie informatique, Cellules HEK293, Cellules Vero, Extinction de l'expression des gènes, Facteurs temps, Furine, Humains, Lignée cellulaire tumorale, Mutation, Prédisposition génétique à une maladie, Pénétration virale.
English descriptors
- KwdEn :
- Animals, Cell Line, Tumor, Chlorocebus aethiops, Computational Biology, Furin (chemistry), Gene Silencing, Genetic Predisposition to Disease, HEK293 Cells, Humans, Middle East Respiratory Syndrome Coronavirus (physiology), Mutation, Peptide Hydrolases (metabolism), RNA, Small Interfering (metabolism), Receptors, Virus (metabolism), Spike Glycoprotein, Coronavirus (metabolism), Time Factors, Vero Cells, Virus Internalization.
- MESH :
- chemical , chemistry : Furin.
- chemical , metabolism : Peptide Hydrolases, RNA, Small Interfering, Receptors, Virus, Spike Glycoprotein, Coronavirus.
- physiology : Middle East Respiratory Syndrome Coronavirus.
- Animals, Cell Line, Tumor, Chlorocebus aethiops, Computational Biology, Gene Silencing, Genetic Predisposition to Disease, HEK293 Cells, Humans, Mutation, Time Factors, Vero Cells, Virus Internalization.
Abstract
Middle East respiratory syndrome coronavirus (MERS-CoV) is a newly identified betacoronavirus causing high morbidity and mortality in humans. The coronavirus spike (S) protein is the main determinant of viral entry, and although it was previously shown that MERS-CoV S can be activated by various proteases, the details of the mechanisms of proteolytic activation of fusion are still incompletely characterized. Here, we have uncovered distinctive characteristics of MERS-CoV S. We identify, by bioinformatics and peptide cleavage assays, two cleavage sites for furin, a ubiquitously expressed protease, which are located at the S1/S2 interface and at the S2' position of the S protein. We show that although the S1/S2 site is proteolytically processed by furin during protein biosynthesis, the S2' site is cleaved upon viral entry. MERS-CoV pseudovirion infection was shown to be enhanced by elevated levels of furin expression, and entry could be decreased by furin siRNA silencing. Enhanced furin activity appeared to partially override the low pH-dependent nature of MERS-CoV entry. Inhibition of furin activity was shown to decrease MERS-CoV S-mediated entry, as well as infection by the virus. Overall, we show that MERS-CoV has evolved an unusual two-step furin activation for fusion, suggestive of a role during the process of emergence into the human population. The ability of MERS-CoV to use furin in this manner, along with other proteases, may explain the polytropic nature of the virus.
DOI: 10.1073/pnas.1407087111
PubMed: 25288733
Affiliations:
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Whittaker</name><affiliation wicri:level="4"><nlm:affiliation>Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14853 grw7@cornell.edu.</nlm:affiliation><country wicri:rule="url">États-Unis</country><wicri:regionArea>Department of Microbiology and Immunology, Cornell University, Ithaca</wicri:regionArea><orgName type="university">Université Cornell</orgName><placeName><settlement type="city">Ithaca (New York)</settlement><region type="state">État de New York</region></placeName></affiliation></author></analytic><series><title level="j">Proceedings of the National Academy of Sciences of the United States of America</title><idno type="eISSN">1091-6490</idno><imprint><date when="2014" type="published">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Cell Line, Tumor</term><term>Chlorocebus aethiops</term><term>Computational Biology</term><term>Furin (chemistry)</term><term>Gene Silencing</term><term>Genetic Predisposition to Disease</term><term>HEK293 Cells</term><term>Humans</term><term>Middle East Respiratory Syndrome Coronavirus (physiology)</term><term>Mutation</term><term>Peptide Hydrolases (metabolism)</term><term>RNA, Small Interfering (metabolism)</term><term>Receptors, Virus (metabolism)</term><term>Spike Glycoprotein, Coronavirus (metabolism)</term><term>Time Factors</term><term>Vero Cells</term><term>Virus Internalization</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term><term>Biologie informatique</term><term>Cellules HEK293</term><term>Cellules Vero</term><term>Coronavirus du syndrome respiratoire du Moyen-Orient (physiologie)</term><term>Extinction de l'expression des gènes</term><term>Facteurs temps</term><term>Furine ()</term><term>Glycoprotéine de spicule des coronavirus (métabolisme)</term><term>Humains</term><term>Lignée cellulaire tumorale</term><term>Mutation</term><term>Peptide hydrolases (métabolisme)</term><term>Petit ARN interférent (métabolisme)</term><term>Prédisposition génétique à une maladie</term><term>Pénétration virale</term><term>Récepteurs viraux (métabolisme)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Furin</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Peptide Hydrolases</term><term>RNA, Small Interfering</term><term>Receptors, Virus</term><term>Spike Glycoprotein, Coronavirus</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Glycoprotéine de spicule des coronavirus</term><term>Peptide hydrolases</term><term>Petit ARN interférent</term><term>Récepteurs viraux</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Coronavirus du syndrome respiratoire du Moyen-Orient</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Middle East Respiratory Syndrome Coronavirus</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Cell Line, Tumor</term><term>Chlorocebus aethiops</term><term>Computational Biology</term><term>Gene Silencing</term><term>Genetic Predisposition to Disease</term><term>HEK293 Cells</term><term>Humans</term><term>Mutation</term><term>Time Factors</term><term>Vero Cells</term><term>Virus Internalization</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Biologie informatique</term><term>Cellules HEK293</term><term>Cellules Vero</term><term>Extinction de l'expression des gènes</term><term>Facteurs temps</term><term>Furine</term><term>Humains</term><term>Lignée cellulaire tumorale</term><term>Mutation</term><term>Prédisposition génétique à une maladie</term><term>Pénétration virale</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Middle East respiratory syndrome coronavirus (MERS-CoV) is a newly identified betacoronavirus causing high morbidity and mortality in humans. The coronavirus spike (S) protein is the main determinant of viral entry, and although it was previously shown that MERS-CoV S can be activated by various proteases, the details of the mechanisms of proteolytic activation of fusion are still incompletely characterized. Here, we have uncovered distinctive characteristics of MERS-CoV S. We identify, by bioinformatics and peptide cleavage assays, two cleavage sites for furin, a ubiquitously expressed protease, which are located at the S1/S2 interface and at the S2' position of the S protein. We show that although the S1/S2 site is proteolytically processed by furin during protein biosynthesis, the S2' site is cleaved upon viral entry. MERS-CoV pseudovirion infection was shown to be enhanced by elevated levels of furin expression, and entry could be decreased by furin siRNA silencing. Enhanced furin activity appeared to partially override the low pH-dependent nature of MERS-CoV entry. Inhibition of furin activity was shown to decrease MERS-CoV S-mediated entry, as well as infection by the virus. Overall, we show that MERS-CoV has evolved an unusual two-step furin activation for fusion, suggestive of a role during the process of emergence into the human population. The ability of MERS-CoV to use furin in this manner, along with other proteases, may explain the polytropic nature of the virus. </div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>État de New York</li></region><settlement><li>Ithaca (New York)</li></settlement><orgName><li>Université Cornell</li></orgName></list><tree><country name="États-Unis"><region name="État de New York"><name sortKey="Millet, Jean Kaoru" sort="Millet, Jean Kaoru" uniqKey="Millet J" first="Jean Kaoru" last="Millet">Jean Kaoru Millet</name></region><name sortKey="Whittaker, Gary R" sort="Whittaker, Gary R" uniqKey="Whittaker G" first="Gary R" last="Whittaker">Gary R. 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