Coronavirus Nsp10, a critical co-factor for activation of multiple replicative enzymes.
Identifieur interne : 001682 ( Main/Exploration ); précédent : 001681; suivant : 001683Coronavirus Nsp10, a critical co-factor for activation of multiple replicative enzymes.
Auteurs : Mickaël Bouvet [France] ; Adrien Lugari [France] ; Clara C. Posthuma [Pays-Bas] ; Jessika C. Zevenhoven [Pays-Bas] ; Stéphanie Bernard [France] ; Stéphane Betzi [France] ; Isabelle Imbert [France] ; Bruno Canard [France] ; Jean-Claude Guillemot [France] ; Patrick Lécine ; Susanne Pfefferle [Allemagne] ; Christian Drosten [Allemagne] ; Eric J. Snijder [Pays-Bas] ; Etienne Decroly [France] ; Xavier Morelli [France]Source :
- The Journal of biological chemistry [ 1083-351X ] ; 2014.
Descripteurs français
- KwdFr :
- Cartes d'interactions protéiques (génétique), Cristallographie aux rayons X, Exoribonucleases (génétique), Exoribonucleases (métabolisme), Humains, Infections à coronavirus (anatomopathologie), Infections à coronavirus (enzymologie), Methyltransferases (génétique), Methyltransferases (métabolisme), Mutagenèse, Protéines d'archée (génétique), Protéines d'archée (métabolisme), Protéines virales non structurales (génétique), Protéines virales non structurales (métabolisme), Réplication virale (génétique), Virus du SRAS (enzymologie).
- MESH :
- anatomopathologie : Infections à coronavirus.
- enzymologie : Infections à coronavirus, Virus du SRAS.
- génétique : Cartes d'interactions protéiques, Exoribonucleases, Methyltransferases, Protéines d'archée, Protéines virales non structurales, Réplication virale.
- métabolisme : Exoribonucleases, Methyltransferases, Protéines d'archée, Protéines virales non structurales.
- Cristallographie aux rayons X, Humains, Mutagenèse.
- Wicri :
- topic : Génétique.
English descriptors
- KwdEn :
- Archaeal Proteins (genetics), Archaeal Proteins (metabolism), Coronavirus Infections (enzymology), Coronavirus Infections (pathology), Crystallography, X-Ray, Exoribonucleases (genetics), Exoribonucleases (metabolism), Humans, Methyltransferases (genetics), Methyltransferases (metabolism), Mutagenesis, Protein Interaction Maps (genetics), SARS Virus (enzymology), Viral Nonstructural Proteins (genetics), Viral Nonstructural Proteins (metabolism), Virus Replication (genetics).
- MESH :
- chemical , genetics : Archaeal Proteins, Exoribonucleases, Methyltransferases, Viral Nonstructural Proteins.
- chemical , metabolism : Archaeal Proteins, Exoribonucleases, Methyltransferases, Viral Nonstructural Proteins.
- enzymology : Coronavirus Infections, SARS Virus.
- genetics : Protein Interaction Maps, Virus Replication.
- pathology : Coronavirus Infections.
- Crystallography, X-Ray, Humans, Mutagenesis.
- mix :
- Archaeal Proteins, Coronavirus Infections, Crystallography, Exoribonucleases, Genetics, Humans, Methyltransferases, Mutagenesis, Protein Interaction Maps, Protein-Protein Interaction, RNA Methyltransferase, RNA Virus, SARS Virus, Viral Nonstructural Proteins, Viral Replication, Viral Transcription, Virus Replication, X-Ray.
Abstract
The RNA-synthesizing machinery of the severe acute respiratory syndrome Coronavirus (SARS-CoV) is composed of 16 non-structural proteins (nsp1-16) encoded by ORF1a/1b. The 148-amino acid nsp10 subunit contains two zinc fingers and is known to interact with both nsp14 and nsp16, stimulating their respective 3'-5' exoribonuclease and 2'-O-methyltransferase activities. Using alanine-scanning mutagenesis, in cellulo bioluminescence resonance energy transfer experiments, and in vitro pulldown assays, we have now identified the key residues on the nsp10 surface that interact with nsp14. The functional consequences of mutations introduced at these positions were first evaluated biochemically by monitoring nsp14 exoribonuclease activity. Disruption of the nsp10-nsp14 interaction abrogated the nsp10-driven activation of the nsp14 exoribonuclease. We further showed that the nsp10 surface interacting with nsp14 overlaps with the surface involved in the nsp10-mediated activation of nsp16 2'-O-methyltransferase activity, suggesting that nsp10 is a major regulator of SARS-CoV replicase function. In line with this notion, reverse genetics experiments supported an essential role of the nsp10 surface that interacts with nsp14 in SARS-CoV replication, as several mutations that abolished the interaction in vitro yielded a replication-negative viral phenotype. In contrast, mutants in which the nsp10-nsp16 interaction was disturbed proved to be crippled but viable. These experiments imply that the nsp10 surface that interacts with nsp14 and nsp16 and possibly other subunits of the viral replication complex may be a target for the development of antiviral compounds against pathogenic coronaviruses.
Url:
DOI: 10.1074/jbc.M114.577353
PubMed: 25074927
Affiliations:
- Allemagne, France, Pays-Bas
- District de Cologne, Hollande-Méridionale, Provence-Alpes-Côte d'Azur, Rhénanie-du-Nord-Westphalie
- Bonn, Leyde, Marseille
- Université d'Aix-Marseille
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Le document en format XML
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Posthuma</name><affiliation wicri:level="1"><nlm:affiliation>Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, P. O. Box 9600, 2300RC Leiden, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, P. O. Box 9600, 2300RC Leiden</wicri:regionArea><placeName><settlement type="city">Leyde</settlement><region nuts="2" type="province">Hollande-Méridionale</region></placeName></affiliation></author><author><name sortKey="Zevenhoven, Jessika C" sort="Zevenhoven, Jessika C" uniqKey="Zevenhoven J" first="Jessika C" last="Zevenhoven">Jessika C. Zevenhoven</name><affiliation wicri:level="1"><nlm:affiliation>Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, P. O. 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wicri:level="3"><nlm:affiliation>From the Aix-Marseille Université, AFMB UMR 7257, 13288 Marseille, France, CNRS, AFMB UMR 7257, 13288 Marseille, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>From the Aix-Marseille Université, AFMB UMR 7257, 13288 Marseille, France, CNRS, AFMB UMR 7257, 13288 Marseille</wicri:regionArea><placeName><region type="region" nuts="2">Provence-Alpes-Côte d'Azur</region><settlement type="city">Marseille</settlement></placeName></affiliation></author><author><name sortKey="Canard, Bruno" sort="Canard, Bruno" uniqKey="Canard B" first="Bruno" last="Canard">Bruno Canard</name><affiliation wicri:level="3"><nlm:affiliation>From the Aix-Marseille Université, AFMB UMR 7257, 13288 Marseille, France, CNRS, AFMB UMR 7257, 13288 Marseille, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>From the Aix-Marseille Université, AFMB UMR 7257, 13288 Marseille, France, CNRS, AFMB UMR 7257, 13288 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Lécine</name><affiliation><nlm:affiliation>CIRI, INSERM U1111, CNRS UMR5308, Université Lyon 1, ENS de Lyon, 69007 Lyon, France, and.</nlm:affiliation><wicri:noCountry code="subField">and</wicri:noCountry></affiliation></author><author><name sortKey="Pfefferle, Susanne" sort="Pfefferle, Susanne" uniqKey="Pfefferle S" first="Susanne" last="Pfefferle">Susanne Pfefferle</name><affiliation wicri:level="3"><nlm:affiliation>Institute of Virology, University of Bonn Medical Center, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Virology, University of Bonn Medical Center, Sigmund-Freud-Strasse 25, 53127 Bonn</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Bonn</settlement></placeName></affiliation></author><author><name sortKey="Drosten, Christian" sort="Drosten, Christian" 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Posthuma</name><affiliation wicri:level="1"><nlm:affiliation>Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, P. O. Box 9600, 2300RC Leiden, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, P. O. Box 9600, 2300RC Leiden</wicri:regionArea><placeName><settlement type="city">Leyde</settlement><region nuts="2" type="province">Hollande-Méridionale</region></placeName></affiliation></author><author><name sortKey="Zevenhoven, Jessika C" sort="Zevenhoven, Jessika C" uniqKey="Zevenhoven J" first="Jessika C" last="Zevenhoven">Jessika C. Zevenhoven</name><affiliation wicri:level="1"><nlm:affiliation>Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, P. O. Box 9600, 2300RC Leiden, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, P. O. Box 9600, 2300RC Leiden</wicri:regionArea><placeName><settlement type="city">Leyde</settlement><region nuts="2" type="province">Hollande-Méridionale</region></placeName></affiliation></author><author><name sortKey="Bernard, Stephanie" sort="Bernard, Stephanie" uniqKey="Bernard S" first="Stéphanie" last="Bernard">Stéphanie Bernard</name><affiliation wicri:level="4"><nlm:affiliation>Cancer Research Center of Marseille (CRCM), CNRS UMR7258, INSERM U1068, Institut Paoli-Calmettes, Aix-Marseille Université, F-13009 Marseille, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Cancer Research Center of Marseille (CRCM), CNRS UMR7258, INSERM U1068, Institut Paoli-Calmettes, Aix-Marseille Université, F-13009 Marseille</wicri:regionArea><placeName><region type="region" nuts="2">Provence-Alpes-Côte d'Azur</region><settlement type="city">Marseille</settlement></placeName><orgName type="university">Université d'Aix-Marseille</orgName></affiliation></author><author><name sortKey="Betzi, Stephane" sort="Betzi, Stephane" uniqKey="Betzi S" first="Stéphane" last="Betzi">Stéphane Betzi</name><affiliation wicri:level="4"><nlm:affiliation>Cancer Research Center of Marseille (CRCM), CNRS UMR7258, INSERM U1068, Institut Paoli-Calmettes, Aix-Marseille Université, F-13009 Marseille, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Cancer Research Center of Marseille (CRCM), CNRS UMR7258, INSERM U1068, Institut Paoli-Calmettes, Aix-Marseille Université, F-13009 Marseille</wicri:regionArea><placeName><region type="region" nuts="2">Provence-Alpes-Côte d'Azur</region><settlement type="city">Marseille</settlement></placeName><orgName type="university">Université d'Aix-Marseille</orgName></affiliation></author><author><name sortKey="Imbert, Isabelle" sort="Imbert, Isabelle" uniqKey="Imbert I" first="Isabelle" last="Imbert">Isabelle Imbert</name><affiliation wicri:level="3"><nlm:affiliation>From the Aix-Marseille Université, AFMB UMR 7257, 13288 Marseille, France, CNRS, AFMB UMR 7257, 13288 Marseille, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>From the Aix-Marseille Université, AFMB UMR 7257, 13288 Marseille, France, CNRS, AFMB UMR 7257, 13288 Marseille</wicri:regionArea><placeName><region type="region" nuts="2">Provence-Alpes-Côte d'Azur</region><settlement type="city">Marseille</settlement></placeName></affiliation></author><author><name sortKey="Canard, Bruno" sort="Canard, Bruno" uniqKey="Canard B" first="Bruno" last="Canard">Bruno Canard</name><affiliation wicri:level="3"><nlm:affiliation>From the Aix-Marseille Université, AFMB UMR 7257, 13288 Marseille, France, CNRS, AFMB UMR 7257, 13288 Marseille, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>From the Aix-Marseille Université, AFMB UMR 7257, 13288 Marseille, France, CNRS, AFMB UMR 7257, 13288 Marseille</wicri:regionArea><placeName><region type="region" nuts="2">Provence-Alpes-Côte d'Azur</region><settlement type="city">Marseille</settlement></placeName></affiliation></author><author><name sortKey="Guillemot, Jean Claude" sort="Guillemot, Jean Claude" uniqKey="Guillemot J" first="Jean-Claude" last="Guillemot">Jean-Claude Guillemot</name><affiliation wicri:level="3"><nlm:affiliation>From the Aix-Marseille Université, AFMB UMR 7257, 13288 Marseille, France, CNRS, AFMB UMR 7257, 13288 Marseille, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>From the Aix-Marseille Université, AFMB UMR 7257, 13288 Marseille, France, CNRS, AFMB UMR 7257, 13288 Marseille</wicri:regionArea><placeName><region type="region" nuts="2">Provence-Alpes-Côte d'Azur</region><settlement type="city">Marseille</settlement></placeName></affiliation></author><author><name sortKey="Lecine, Patrick" sort="Lecine, Patrick" uniqKey="Lecine P" first="Patrick" last="Lécine">Patrick Lécine</name><affiliation><nlm:affiliation>CIRI, INSERM U1111, CNRS UMR5308, Université Lyon 1, ENS de Lyon, 69007 Lyon, France, and.</nlm:affiliation><wicri:noCountry code="subField">and</wicri:noCountry></affiliation></author><author><name sortKey="Pfefferle, Susanne" sort="Pfefferle, Susanne" uniqKey="Pfefferle S" first="Susanne" last="Pfefferle">Susanne Pfefferle</name><affiliation wicri:level="3"><nlm:affiliation>Institute of Virology, University of Bonn Medical Center, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Virology, University of Bonn Medical Center, Sigmund-Freud-Strasse 25, 53127 Bonn</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Bonn</settlement></placeName></affiliation></author><author><name sortKey="Drosten, Christian" sort="Drosten, Christian" uniqKey="Drosten C" first="Christian" last="Drosten">Christian Drosten</name><affiliation wicri:level="3"><nlm:affiliation>Institute of Virology, University of Bonn Medical Center, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Virology, University of Bonn Medical Center, Sigmund-Freud-Strasse 25, 53127 Bonn</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Bonn</settlement></placeName></affiliation></author><author><name sortKey="Snijder, Eric J" sort="Snijder, Eric J" uniqKey="Snijder E" first="Eric J" last="Snijder">Eric J. Snijder</name><affiliation wicri:level="1"><nlm:affiliation>Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, P. O. Box 9600, 2300RC Leiden, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, P. O. Box 9600, 2300RC Leiden</wicri:regionArea><placeName><settlement type="city">Leyde</settlement><region nuts="2" type="province">Hollande-Méridionale</region></placeName></affiliation></author><author><name sortKey="Decroly, Etienne" sort="Decroly, Etienne" uniqKey="Decroly E" first="Etienne" last="Decroly">Etienne Decroly</name><affiliation wicri:level="1"><nlm:affiliation>From the Aix-Marseille Université, AFMB UMR 7257, 13288 Marseille, France, CNRS, AFMB UMR 7257, 13288 Marseille, France, etienne.decroly@afmb.univ-mrs.fr.</nlm:affiliation><country wicri:rule="url">France</country><wicri:regionArea>From the Aix-Marseille Université, AFMB UMR 7257, 13288 Marseille, France, CNRS, AFMB UMR 7257, 13288 Marseille, France</wicri:regionArea><wicri:noRegion>France</wicri:noRegion><wicri:noRegion>France</wicri:noRegion></affiliation></author><author><name sortKey="Morelli, Xavier" sort="Morelli, Xavier" uniqKey="Morelli X" first="Xavier" last="Morelli">Xavier Morelli</name><affiliation wicri:level="4"><nlm:affiliation>Cancer Research Center of Marseille (CRCM), CNRS UMR7258, INSERM U1068, Institut Paoli-Calmettes, Aix-Marseille Université, F-13009 Marseille, France, xavier.morelli@inserm.fr.</nlm:affiliation><country wicri:rule="url">France</country><wicri:regionArea>Cancer Research Center of Marseille (CRCM), CNRS UMR7258, INSERM U1068, Institut Paoli-Calmettes, Aix-Marseille Université, F-13009 Marseille, France</wicri:regionArea><wicri:noRegion>France</wicri:noRegion><orgName type="university">Université d'Aix-Marseille</orgName><placeName><settlement type="city">Marseille</settlement><region type="region" nuts="2">Provence-Alpes-Côte d'Azur</region></placeName></affiliation></author></analytic><series><title level="j">The Journal of biological chemistry</title><idno type="eISSN">1083-351X</idno><imprint><date when="2014" type="published">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Archaeal Proteins (genetics)</term><term>Archaeal Proteins (metabolism)</term><term>Coronavirus Infections (enzymology)</term><term>Coronavirus Infections (pathology)</term><term>Crystallography, X-Ray</term><term>Exoribonucleases (genetics)</term><term>Exoribonucleases (metabolism)</term><term>Humans</term><term>Methyltransferases (genetics)</term><term>Methyltransferases (metabolism)</term><term>Mutagenesis</term><term>Protein Interaction Maps (genetics)</term><term>SARS Virus (enzymology)</term><term>Viral Nonstructural Proteins (genetics)</term><term>Viral Nonstructural Proteins (metabolism)</term><term>Virus Replication (genetics)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Cartes d'interactions protéiques (génétique)</term><term>Cristallographie aux rayons X</term><term>Exoribonucleases (génétique)</term><term>Exoribonucleases (métabolisme)</term><term>Humains</term><term>Infections à coronavirus (anatomopathologie)</term><term>Infections à coronavirus (enzymologie)</term><term>Methyltransferases (génétique)</term><term>Methyltransferases (métabolisme)</term><term>Mutagenèse</term><term>Protéines d'archée (génétique)</term><term>Protéines d'archée (métabolisme)</term><term>Protéines virales non structurales (génétique)</term><term>Protéines virales non structurales (métabolisme)</term><term>Réplication virale (génétique)</term><term>Virus du SRAS (enzymologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Archaeal Proteins</term><term>Exoribonucleases</term><term>Methyltransferases</term><term>Viral Nonstructural Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Archaeal Proteins</term><term>Exoribonucleases</term><term>Methyltransferases</term><term>Viral Nonstructural Proteins</term></keywords><keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Infections à coronavirus</term></keywords><keywords scheme="MESH" qualifier="enzymologie" xml:lang="fr"><term>Infections à coronavirus</term><term>Virus du SRAS</term></keywords><keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>Coronavirus Infections</term><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Protein Interaction Maps</term><term>Virus Replication</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Cartes d'interactions protéiques</term><term>Exoribonucleases</term><term>Methyltransferases</term><term>Protéines d'archée</term><term>Protéines virales non structurales</term><term>Réplication virale</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Exoribonucleases</term><term>Methyltransferases</term><term>Protéines d'archée</term><term>Protéines virales non structurales</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Coronavirus Infections</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Crystallography, X-Ray</term><term>Humans</term><term>Mutagenesis</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Cristallographie aux rayons X</term><term>Humains</term><term>Mutagenèse</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Génétique</term></keywords><keywords scheme="mix" xml:lang="en"><term>Archaeal Proteins</term><term>Coronavirus Infections</term><term>Crystallography</term><term>Exoribonucleases</term><term>Genetics</term><term>Humans</term><term>Methyltransferases</term><term>Mutagenesis</term><term>Protein Interaction Maps</term><term>Protein-Protein Interaction</term><term>RNA Methyltransferase</term><term>RNA Virus</term><term>SARS Virus</term><term>Viral Nonstructural Proteins</term><term>Viral Replication</term><term>Viral Transcription</term><term>Virus Replication</term><term>X-Ray</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The RNA-synthesizing machinery of the severe acute respiratory syndrome Coronavirus (SARS-CoV) is composed of 16 non-structural proteins (nsp1-16) encoded by ORF1a/1b. The 148-amino acid nsp10 subunit contains two zinc fingers and is known to interact with both nsp14 and nsp16, stimulating their respective 3'-5' exoribonuclease and 2'-O-methyltransferase activities. Using alanine-scanning mutagenesis, in cellulo bioluminescence resonance energy transfer experiments, and in vitro pulldown assays, we have now identified the key residues on the nsp10 surface that interact with nsp14. The functional consequences of mutations introduced at these positions were first evaluated biochemically by monitoring nsp14 exoribonuclease activity. Disruption of the nsp10-nsp14 interaction abrogated the nsp10-driven activation of the nsp14 exoribonuclease. We further showed that the nsp10 surface interacting with nsp14 overlaps with the surface involved in the nsp10-mediated activation of nsp16 2'-O-methyltransferase activity, suggesting that nsp10 is a major regulator of SARS-CoV replicase function. In line with this notion, reverse genetics experiments supported an essential role of the nsp10 surface that interacts with nsp14 in SARS-CoV replication, as several mutations that abolished the interaction in vitro yielded a replication-negative viral phenotype. In contrast, mutants in which the nsp10-nsp16 interaction was disturbed proved to be crippled but viable. These experiments imply that the nsp10 surface that interacts with nsp14 and nsp16 and possibly other subunits of the viral replication complex may be a target for the development of antiviral compounds against pathogenic coronaviruses. </div></front></TEI><affiliations><list><country><li>Allemagne</li><li>France</li><li>Pays-Bas</li></country><region><li>District de Cologne</li><li>Hollande-Méridionale</li><li>Provence-Alpes-Côte d'Azur</li><li>Rhénanie-du-Nord-Westphalie</li></region><settlement><li>Bonn</li><li>Leyde</li><li>Marseille</li></settlement><orgName><li>Université d'Aix-Marseille</li></orgName></list><tree><noCountry><name sortKey="Lecine, Patrick" sort="Lecine, Patrick" uniqKey="Lecine P" first="Patrick" last="Lécine">Patrick Lécine</name></noCountry><country name="France"><region name="Provence-Alpes-Côte d'Azur"><name sortKey="Bouvet, Mickael" sort="Bouvet, Mickael" uniqKey="Bouvet M" first="Mickaël" last="Bouvet">Mickaël Bouvet</name></region><name sortKey="Bernard, Stephanie" sort="Bernard, Stephanie" uniqKey="Bernard S" first="Stéphanie" last="Bernard">Stéphanie Bernard</name><name sortKey="Betzi, Stephane" sort="Betzi, Stephane" uniqKey="Betzi S" first="Stéphane" last="Betzi">Stéphane Betzi</name><name sortKey="Canard, Bruno" sort="Canard, Bruno" uniqKey="Canard B" first="Bruno" last="Canard">Bruno Canard</name><name sortKey="Decroly, Etienne" sort="Decroly, Etienne" uniqKey="Decroly E" first="Etienne" last="Decroly">Etienne Decroly</name><name sortKey="Guillemot, Jean Claude" sort="Guillemot, Jean Claude" uniqKey="Guillemot J" first="Jean-Claude" last="Guillemot">Jean-Claude Guillemot</name><name sortKey="Imbert, Isabelle" sort="Imbert, Isabelle" uniqKey="Imbert I" first="Isabelle" last="Imbert">Isabelle Imbert</name><name sortKey="Lugari, Adrien" sort="Lugari, Adrien" uniqKey="Lugari A" first="Adrien" last="Lugari">Adrien Lugari</name><name sortKey="Morelli, Xavier" sort="Morelli, Xavier" uniqKey="Morelli X" first="Xavier" last="Morelli">Xavier Morelli</name></country><country name="Pays-Bas"><region name="Hollande-Méridionale"><name sortKey="Posthuma, Clara C" sort="Posthuma, Clara C" uniqKey="Posthuma C" first="Clara C" last="Posthuma">Clara C. Posthuma</name></region><name sortKey="Snijder, Eric J" sort="Snijder, Eric J" uniqKey="Snijder E" first="Eric J" last="Snijder">Eric J. Snijder</name><name sortKey="Zevenhoven, Jessika C" sort="Zevenhoven, Jessika C" uniqKey="Zevenhoven J" first="Jessika C" last="Zevenhoven">Jessika C. Zevenhoven</name></country><country name="Allemagne"><region name="Rhénanie-du-Nord-Westphalie"><name sortKey="Pfefferle, Susanne" sort="Pfefferle, Susanne" uniqKey="Pfefferle S" first="Susanne" last="Pfefferle">Susanne Pfefferle</name></region><name sortKey="Drosten, Christian" sort="Drosten, Christian" uniqKey="Drosten C" first="Christian" last="Drosten">Christian Drosten</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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