The tetraspanin CD9 facilitates MERS-coronavirus entry by scaffolding host cell receptors and proteases
Identifieur interne : 000B43 ( Main/Exploration ); précédent : 000B42; suivant : 000B44The tetraspanin CD9 facilitates MERS-coronavirus entry by scaffolding host cell receptors and proteases
Auteurs : James T. Earnest [États-Unis] ; Michael P. Hantak [États-Unis] ; Kun Li [États-Unis] ; Paul B. Mccray [États-Unis] ; Stanley Perlman [États-Unis] ; Tom Gallagher [États-Unis]Source :
- PLoS Pathogens [ 1553-7366 ] ; 2017.
Descripteurs français
- KwdFr :
- Animaux, Coronavirus du syndrome respiratoire du Moyen-Orient (génétique), Coronavirus du syndrome respiratoire du Moyen-Orient (physiologie), Dipeptidyl peptidase 4 (génétique), Dipeptidyl peptidase 4 (métabolisme), Glycoprotéine de spicule des coronavirus (génétique), Glycoprotéine de spicule des coronavirus (métabolisme), Humains, Infections à coronavirus (enzymologie), Infections à coronavirus (génétique), Infections à coronavirus (métabolisme), Infections à coronavirus (virologie), Pénétration virale, Récepteurs viraux (génétique), Récepteurs viraux (métabolisme), Serine endopeptidases (génétique), Serine endopeptidases (métabolisme), Souris.
- MESH :
- enzymologie : Infections à coronavirus.
- génétique : Coronavirus du syndrome respiratoire du Moyen-Orient, Dipeptidyl peptidase 4, Glycoprotéine de spicule des coronavirus, Infections à coronavirus, Récepteurs viraux, Serine endopeptidases.
- métabolisme : Dipeptidyl peptidase 4, Glycoprotéine de spicule des coronavirus, Infections à coronavirus, Récepteurs viraux, Serine endopeptidases.
- physiologie : Coronavirus du syndrome respiratoire du Moyen-Orient.
- virologie : Infections à coronavirus.
- Animaux, Humains, Pénétration virale, Souris.
English descriptors
- KwdEn :
- Animals, Coronavirus Infections (enzymology), Coronavirus Infections (genetics), Coronavirus Infections (metabolism), Coronavirus Infections (virology), Dipeptidyl Peptidase 4 (genetics), Dipeptidyl Peptidase 4 (metabolism), Humans, Mice, Middle East Respiratory Syndrome Coronavirus (genetics), Middle East Respiratory Syndrome Coronavirus (physiology), Receptors, Virus (genetics), Receptors, Virus (metabolism), Serine Endopeptidases (genetics), Serine Endopeptidases (metabolism), Spike Glycoprotein, Coronavirus (genetics), Spike Glycoprotein, Coronavirus (metabolism), Tetraspanin 28 (genetics), Tetraspanin 28 (metabolism), Tetraspanin 29 (genetics), Tetraspanin 29 (metabolism), Virus Internalization.
- MESH :
- chemical , genetics : Dipeptidyl Peptidase 4, Receptors, Virus, Serine Endopeptidases, Spike Glycoprotein, Coronavirus, Tetraspanin 28, Tetraspanin 29.
- enzymology : Coronavirus Infections.
- genetics : Coronavirus Infections, Middle East Respiratory Syndrome Coronavirus.
- metabolism : Coronavirus Infections, Dipeptidyl Peptidase 4, Receptors, Virus, Serine Endopeptidases, Spike Glycoprotein, Coronavirus, Tetraspanin 28, Tetraspanin 29.
- physiology : Middle East Respiratory Syndrome Coronavirus.
- virology : Coronavirus Infections.
- Animals, Humans, Mice, Virus Internalization.
Abstract
Infection by enveloped coronaviruses (CoVs) initiates with viral spike (S) proteins binding to cellular receptors, and is followed by proteolytic cleavage of receptor-bound S proteins, which prompts S protein-mediated virus-cell membrane fusion. Infection therefore requires close proximity of receptors and proteases. We considered whether tetraspanins, scaffolding proteins known to facilitate CoV infections, hold receptors and proteases together on cell membranes. Using knockout cell lines, we found that the tetraspanin CD9, but not the tetraspanin CD81, formed cell-surface complexes of dipeptidyl peptidase 4 (DPP4), the MERS-CoV receptor, and the type II transmembrane serine protease (TTSP) member TMPRSS2, a CoV-activating protease. This CD9-facilitated condensation of receptors and proteases allowed MERS-CoV pseudoviruses to enter cells rapidly and efficiently. Without CD9, MERS-CoV viruses were not activated by TTSPs, and they trafficked into endosomes to be cleaved much later and less efficiently by cathepsins. Thus, we identified DPP4:CD9:TTSP as the protein complexes necessary for early, efficient MERS-CoV entry. To evaluate the importance of these complexes in an
Url:
DOI: 10.1371/journal.ppat.1006546
PubMed: 28759649
PubMed Central: 5552337
Affiliations:
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Le document en format XML
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Medicine, University of Iowa, Iowa City, IA</wicri:regionArea><placeName><region type="state">Iowa</region><settlement type="city">Iowa City</settlement></placeName><orgName type="university">Université de l'Iowa</orgName></affiliation><affiliation wicri:level="4"><nlm:aff id="aff003"><addr-line>Department of Microbiology, University of Iowa, Iowa City, IA, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Microbiology, University of Iowa, Iowa City, IA</wicri:regionArea><placeName><region type="state">Iowa</region><settlement type="city">Iowa City</settlement></placeName><orgName type="university">Université de l'Iowa</orgName></affiliation></author><author><name sortKey="Gallagher, Tom" sort="Gallagher, Tom" uniqKey="Gallagher T" first="Tom" last="Gallagher">Tom Gallagher</name><affiliation wicri:level="2"><nlm:aff id="aff001"><addr-line>Department of Microbiology and Immunology, Loyola University Medical Center, Maywood, IL, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Microbiology and Immunology, Loyola University Medical Center, Maywood, IL</wicri:regionArea><placeName><region type="state">Illinois</region></placeName></affiliation></author></analytic><series><title level="j">PLoS Pathogens</title><idno type="ISSN">1553-7366</idno><idno type="eISSN">1553-7374</idno><imprint><date when="2017">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Coronavirus Infections (enzymology)</term><term>Coronavirus Infections (genetics)</term><term>Coronavirus Infections (metabolism)</term><term>Coronavirus Infections (virology)</term><term>Dipeptidyl Peptidase 4 (genetics)</term><term>Dipeptidyl Peptidase 4 (metabolism)</term><term>Humans</term><term>Mice</term><term>Middle East Respiratory Syndrome Coronavirus (genetics)</term><term>Middle East Respiratory Syndrome Coronavirus (physiology)</term><term>Receptors, Virus (genetics)</term><term>Receptors, Virus (metabolism)</term><term>Serine Endopeptidases (genetics)</term><term>Serine Endopeptidases (metabolism)</term><term>Spike Glycoprotein, Coronavirus (genetics)</term><term>Spike Glycoprotein, Coronavirus (metabolism)</term><term>Tetraspanin 28 (genetics)</term><term>Tetraspanin 28 (metabolism)</term><term>Tetraspanin 29 (genetics)</term><term>Tetraspanin 29 (metabolism)</term><term>Virus Internalization</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term><term>Coronavirus du syndrome respiratoire du Moyen-Orient (génétique)</term><term>Coronavirus du syndrome respiratoire du Moyen-Orient (physiologie)</term><term>Dipeptidyl peptidase 4 (génétique)</term><term>Dipeptidyl peptidase 4 (métabolisme)</term><term>Glycoprotéine de spicule des coronavirus (génétique)</term><term>Glycoprotéine de spicule des coronavirus (métabolisme)</term><term>Humains</term><term>Infections à coronavirus (enzymologie)</term><term>Infections à coronavirus (génétique)</term><term>Infections à coronavirus (métabolisme)</term><term>Infections à coronavirus (virologie)</term><term>Pénétration virale</term><term>Récepteurs viraux (génétique)</term><term>Récepteurs viraux (métabolisme)</term><term>Serine endopeptidases (génétique)</term><term>Serine endopeptidases (métabolisme)</term><term>Souris</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Dipeptidyl Peptidase 4</term><term>Receptors, Virus</term><term>Serine Endopeptidases</term><term>Spike Glycoprotein, Coronavirus</term><term>Tetraspanin 28</term><term>Tetraspanin 29</term></keywords><keywords scheme="MESH" qualifier="enzymologie" xml:lang="fr"><term>Infections à coronavirus</term></keywords><keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>Coronavirus Infections</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Coronavirus Infections</term><term>Middle East Respiratory Syndrome Coronavirus</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Coronavirus du syndrome respiratoire du Moyen-Orient</term><term>Dipeptidyl peptidase 4</term><term>Glycoprotéine de spicule des coronavirus</term><term>Infections à coronavirus</term><term>Récepteurs viraux</term><term>Serine endopeptidases</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Coronavirus Infections</term><term>Dipeptidyl Peptidase 4</term><term>Receptors, Virus</term><term>Serine Endopeptidases</term><term>Spike Glycoprotein, Coronavirus</term><term>Tetraspanin 28</term><term>Tetraspanin 29</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Dipeptidyl peptidase 4</term><term>Glycoprotéine de spicule des coronavirus</term><term>Infections à coronavirus</term><term>Récepteurs viraux</term><term>Serine endopeptidases</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" qualifier="virologie" xml:lang="fr"><term>Infections à coronavirus</term></keywords><keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>Coronavirus Infections</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Humans</term><term>Mice</term><term>Virus Internalization</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Humains</term><term>Pénétration virale</term><term>Souris</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Infection by enveloped coronaviruses (CoVs) initiates with viral spike (S) proteins binding to cellular receptors, and is followed by proteolytic cleavage of receptor-bound S proteins, which prompts S protein-mediated virus-cell membrane fusion. Infection therefore requires close proximity of receptors and proteases. We considered whether tetraspanins, scaffolding proteins known to facilitate CoV infections, hold receptors and proteases together on cell membranes. Using knockout cell lines, we found that the tetraspanin CD9, but not the tetraspanin CD81, formed cell-surface complexes of dipeptidyl peptidase 4 (DPP4), the MERS-CoV receptor, and the type II transmembrane serine protease (TTSP) member TMPRSS2, a CoV-activating protease. This CD9-facilitated condensation of receptors and proteases allowed MERS-CoV pseudoviruses to enter cells rapidly and efficiently. Without CD9, MERS-CoV viruses were not activated by TTSPs, and they trafficked into endosomes to be cleaved much later and less efficiently by cathepsins. Thus, we identified DPP4:CD9:TTSP as the protein complexes necessary for early, efficient MERS-CoV entry. To evaluate the importance of these complexes in an <italic>in vivo</italic> CoV infection model, we used recombinant Adenovirus 5 (rAd5) vectors to express human DPP4 in mouse lungs, thereby sensitizing the animals to MERS-CoV infection. When the rAd5-hDPP4 vectors co-expressed small RNAs silencing <italic>Cd9</italic> or <italic>Tmprss2</italic>, the animals were significantly less susceptible, indicating that CD9 and TMPRSS2 facilitated robust <italic>in vivo</italic> MERS-CoV infection of mouse lungs. Furthermore, the S proteins of virulent mouse-adapted MERS-CoVs acquired a CD9-dependent cell entry character, suggesting that CD9 is a selective agent in the evolution of CoV virulence.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Bottcher Friebertshauser, E" uniqKey="Bottcher Friebertshauser E">E Bottcher-Friebertshauser</name></author><author><name sortKey="Freuer, C" uniqKey="Freuer C">C Freuer</name></author><author><name sortKey="Sielaff, F" uniqKey="Sielaff F">F Sielaff</name></author><author><name sortKey="Schmidt, S" uniqKey="Schmidt S">S Schmidt</name></author><author><name sortKey="Eickmann, M" uniqKey="Eickmann M">M Eickmann</name></author><author><name sortKey="Uhlendorff, J" uniqKey="Uhlendorff J">J Uhlendorff</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mothes, W" uniqKey="Mothes W">W Mothes</name></author><author><name sortKey="Boerger, Al" uniqKey="Boerger A">AL 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Campbell</name></author><author><name sortKey="Perez, O" uniqKey="Perez O">O Perez</name></author><author><name sortKey="Melar, M" uniqKey="Melar M">M Melar</name></author><author><name sortKey="Hope, Tj" uniqKey="Hope T">TJ Hope</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Illinois</li><li>Iowa</li></region><settlement><li>Iowa City</li></settlement><orgName><li>Université de l'Iowa</li></orgName></list><tree><country name="États-Unis"><region name="Illinois"><name sortKey="Earnest, James T" sort="Earnest, James T" uniqKey="Earnest J" first="James T." last="Earnest">James T. Earnest</name></region><name sortKey="Gallagher, Tom" sort="Gallagher, Tom" uniqKey="Gallagher T" first="Tom" last="Gallagher">Tom Gallagher</name><name sortKey="Hantak, Michael P" sort="Hantak, Michael P" uniqKey="Hantak M" first="Michael P." last="Hantak">Michael P. Hantak</name><name sortKey="Li, Kun" sort="Li, Kun" uniqKey="Li K" first="Kun" last="Li">Kun Li</name><name sortKey="Mccray, Paul B" sort="Mccray, Paul B" uniqKey="Mccray P" first="Paul B." last="Mccray">Paul B. Mccray</name><name sortKey="Perlman, Stanley" sort="Perlman, Stanley" uniqKey="Perlman S" first="Stanley" last="Perlman">Stanley Perlman</name><name sortKey="Perlman, Stanley" sort="Perlman, Stanley" uniqKey="Perlman S" first="Stanley" last="Perlman">Stanley Perlman</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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