p53 down-regulates SARS coronavirus replication and is targeted by the SARS-unique domain and PLpro via E3 ubiquitin ligase RCHY1.
Identifieur interne : 000F37 ( Main/Exploration ); précédent : 000F36; suivant : 000F38p53 down-regulates SARS coronavirus replication and is targeted by the SARS-unique domain and PLpro via E3 ubiquitin ligase RCHY1.
Auteurs : Yue Ma-Lauer [Allemagne] ; Javier Carbajo-Lozoya [Allemagne] ; Marco Y. Hein [Allemagne] ; Marcel A. Müller [Allemagne] ; Wen Deng [Allemagne] ; Jian Lei [Allemagne] ; Benjamin Meyer [Allemagne] ; Yuri Kusov [Allemagne] ; Brigitte Von Brunn [Allemagne] ; Dev Raj Bairad [Allemagne] ; Sabine Hünten [Allemagne] ; Christian Drosten [Allemagne] ; Heiko Hermeking [Allemagne] ; Heinrich Leonhardt [Allemagne] ; Matthias Mann [Allemagne] ; Rolf Hilgenfeld [Allemagne] ; Albrecht Von Brunn [Allemagne]Source :
- Proceedings of the National Academy of Sciences of the United States of America [ 1091-6490 ] ; 2016.
Descripteurs français
- KwdFr :
- Calcium-Calmodulin-Dependent Protein Kinase Type 2 (génétique), Calcium-Calmodulin-Dependent Protein Kinase Type 2 (métabolisme), Cysteine endopeptidases (génétique), Cysteine endopeptidases (métabolisme), Humains, Interactions hôte-pathogène, Liaison aux protéines, Protéine p53 suppresseur de tumeur (métabolisme), Protéines virales (génétique), Protéines virales (métabolisme), Protéines virales non structurales (génétique), Protéines virales non structurales (métabolisme), Régulation négative, Réplication virale (génétique), Sites de fixation (génétique), Syndrome respiratoire aigu sévère (génétique), Syndrome respiratoire aigu sévère (métabolisme), Syndrome respiratoire aigu sévère (virologie), Ubiquitin-protein ligases (génétique), Ubiquitin-protein ligases (métabolisme), Ubiquitinylation, Virus du SRAS (génétique), Virus du SRAS (métabolisme), Virus du SRAS (physiologie).
- MESH :
- génétique : Calcium-Calmodulin-Dependent Protein Kinase Type 2, Cysteine endopeptidases, Protéines virales, Protéines virales non structurales, Réplication virale, Sites de fixation, Syndrome respiratoire aigu sévère, Ubiquitin-protein ligases, Virus du SRAS.
- métabolisme : Calcium-Calmodulin-Dependent Protein Kinase Type 2, Cysteine endopeptidases, Protéine p53 suppresseur de tumeur, Protéines virales, Protéines virales non structurales, Syndrome respiratoire aigu sévère, Ubiquitin-protein ligases, Virus du SRAS.
- physiologie : Virus du SRAS.
- virologie : Syndrome respiratoire aigu sévère.
- Humains, Interactions hôte-pathogène, Liaison aux protéines, Régulation négative, Ubiquitinylation.
English descriptors
- KwdEn :
- Binding Sites (genetics), Calcium-Calmodulin-Dependent Protein Kinase Type 2 (genetics), Calcium-Calmodulin-Dependent Protein Kinase Type 2 (metabolism), Cysteine Endopeptidases (genetics), Cysteine Endopeptidases (metabolism), Down-Regulation, Host-Pathogen Interactions, Humans, Protein Binding, SARS Virus (genetics), SARS Virus (metabolism), SARS Virus (physiology), Severe Acute Respiratory Syndrome (genetics), Severe Acute Respiratory Syndrome (metabolism), Severe Acute Respiratory Syndrome (virology), Tumor Suppressor Protein p53 (metabolism), Ubiquitin-Protein Ligases (genetics), Ubiquitin-Protein Ligases (metabolism), Ubiquitination, Viral Nonstructural Proteins (genetics), Viral Nonstructural Proteins (metabolism), Viral Proteins (genetics), Viral Proteins (metabolism), Virus Replication (genetics).
- MESH :
- chemical , genetics : Calcium-Calmodulin-Dependent Protein Kinase Type 2, Cysteine Endopeptidases, Ubiquitin-Protein Ligases, Viral Nonstructural Proteins, Viral Proteins.
- genetics : Binding Sites, SARS Virus, Severe Acute Respiratory Syndrome, Virus Replication.
- chemical , metabolism : Calcium-Calmodulin-Dependent Protein Kinase Type 2, Cysteine Endopeptidases, SARS Virus, Severe Acute Respiratory Syndrome, Tumor Suppressor Protein p53, Ubiquitin-Protein Ligases, Viral Nonstructural Proteins, Viral Proteins.
- physiology : SARS Virus.
- virology : Severe Acute Respiratory Syndrome.
- Down-Regulation, Host-Pathogen Interactions, Humans, Protein Binding, Ubiquitination.
Abstract
Highly pathogenic severe acute respiratory syndrome coronavirus (SARS-CoV) has developed strategies to inhibit host immune recognition. We identify cellular E3 ubiquitin ligase ring-finger and CHY zinc-finger domain-containing 1 (RCHY1) as an interacting partner of the viral SARS-unique domain (SUD) and papain-like protease (PL(pro)), and, as a consequence, the involvement of cellular p53 as antagonist of coronaviral replication. Residues 95-144 of RCHY1 and 389-652 of SUD (SUD-NM) subdomains are crucial for interaction. Association with SUD increases the stability of RCHY1 and augments RCHY1-mediated ubiquitination as well as degradation of p53. The calcium/calmodulin-dependent protein kinase II delta (CAMK2D), which normally influences RCHY1 stability by phosphorylation, also binds to SUD. In vivo phosphorylation shows that SUD does not regulate phosphorylation of RCHY1 via CAMK2D. Similarly to SUD, the PL(pro)s from SARS-CoV, MERS-CoV, and HCoV-NL63 physically interact with and stabilize RCHY1, and thus trigger degradation of endogenous p53. The SARS-CoV papain-like protease is encoded next to SUD within nonstructural protein 3. A SUD-PL(pro) fusion interacts with RCHY1 more intensively and causes stronger p53 degradation than SARS-CoV PL(pro) alone. We show that p53 inhibits replication of infectious SARS-CoV as well as of replicons and human coronavirus NL63. Hence, human coronaviruses antagonize the viral inhibitor p53 via stabilizing RCHY1 and promoting RCHY1-mediated p53 degradation. SUD functions as an enhancer to strengthen interaction between RCHY1 and nonstructural protein 3, leading to a further increase in in p53 degradation. The significance of these findings is that down-regulation of p53 as a major player in antiviral innate immunity provides a long-sought explanation for delayed activities of respective genes.
DOI: 10.1073/pnas.1603435113
PubMed: 27519799
Affiliations:
- Allemagne
- Bavière, District de Cologne, District de Haute-Bavière, Rhénanie-du-Nord-Westphalie
- Bonn, Munich
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Le document en format XML
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uniqKey="Kusov Y" first="Yuri" last="Kusov">Yuri Kusov</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck and German Center for Infection Research, partner site Luebeck, 23538 Luebeck, Germany;</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck and German Center for Infection Research, partner site Luebeck, 23538 Luebeck</wicri:regionArea><wicri:noRegion>23538 Luebeck</wicri:noRegion><wicri:noRegion>23538 Luebeck</wicri:noRegion><wicri:noRegion>23538 Luebeck</wicri:noRegion></affiliation></author><author><name sortKey="Von Brunn, Brigitte" sort="Von Brunn, Brigitte" uniqKey="Von Brunn B" first="Brigitte" last="Von Brunn">Brigitte Von Brunn</name><affiliation wicri:level="3"><nlm:affiliation>Max-von-Pettenkofer Institute, Ludwig-Maximilians-University Munich and German Center for Infection Research (DZIF), partner site Munich, 80336 Munich, Germany;</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Max-von-Pettenkofer Institute, Ludwig-Maximilians-University Munich and German Center for Infection Research (DZIF), partner site Munich, 80336 Munich</wicri:regionArea><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region><settlement type="city">Munich</settlement></placeName></affiliation></author><author><name sortKey="Bairad, Dev Raj" sort="Bairad, Dev Raj" uniqKey="Bairad D" first="Dev Raj" last="Bairad">Dev Raj Bairad</name><affiliation wicri:level="3"><nlm:affiliation>Max-von-Pettenkofer Institute, Ludwig-Maximilians-University Munich and German Center for Infection Research (DZIF), partner site Munich, 80336 Munich, Germany;</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Max-von-Pettenkofer Institute, Ludwig-Maximilians-University Munich and German Center for Infection Research (DZIF), partner site Munich, 80336 Munich</wicri:regionArea><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region><settlement type="city">Munich</settlement></placeName></affiliation></author><author><name sortKey="Hunten, Sabine" sort="Hunten, Sabine" uniqKey="Hunten S" first="Sabine" last="Hünten">Sabine Hünten</name><affiliation wicri:level="3"><nlm:affiliation>Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-University Munich, 80337 Munich, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-University Munich, 80337 Munich</wicri:regionArea><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region><settlement 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wicri:level="3"><nlm:affiliation>Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-University Munich, 80337 Munich, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-University Munich, 80337 Munich</wicri:regionArea><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region><settlement type="city">Munich</settlement></placeName></affiliation></author><author><name sortKey="Leonhardt, Heinrich" sort="Leonhardt, Heinrich" uniqKey="Leonhardt H" first="Heinrich" last="Leonhardt">Heinrich Leonhardt</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biology and Center for Integrated Protein Science, Ludwig-Maximilians-University Munich, 82152 Planegg-Martinsried, Germany;</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Biology and Center for Integrated Protein Science, Ludwig-Maximilians-University Munich, 82152 Planegg-Martinsried</wicri:regionArea><wicri:noRegion>82152 Planegg-Martinsried</wicri:noRegion><wicri:noRegion>82152 Planegg-Martinsried</wicri:noRegion><wicri:noRegion>82152 Planegg-Martinsried</wicri:noRegion></affiliation></author><author><name sortKey="Mann, Matthias" sort="Mann, Matthias" uniqKey="Mann M" first="Matthias" last="Mann">Matthias Mann</name><affiliation wicri:level="1"><nlm:affiliation>Department of Proteomics and Signal Transduction, Max-Planck Institute of Biochemistry, 82152 Martinsried, Germany;</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Proteomics and Signal Transduction, Max-Planck Institute of Biochemistry, 82152 Martinsried</wicri:regionArea><wicri:noRegion>82152 Martinsried</wicri:noRegion><wicri:noRegion>82152 Martinsried</wicri:noRegion><wicri:noRegion>82152 Martinsried</wicri:noRegion></affiliation></author><author><name sortKey="Hilgenfeld, Rolf" sort="Hilgenfeld, Rolf" uniqKey="Hilgenfeld R" first="Rolf" last="Hilgenfeld">Rolf Hilgenfeld</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck and German Center for Infection Research, partner site Luebeck, 23538 Luebeck, Germany;</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck and German Center for Infection Research, partner site Luebeck, 23538 Luebeck</wicri:regionArea><wicri:noRegion>23538 Luebeck</wicri:noRegion><wicri:noRegion>23538 Luebeck</wicri:noRegion><wicri:noRegion>23538 Luebeck</wicri:noRegion></affiliation></author><author><name sortKey="Von Brunn, Albrecht" sort="Von Brunn, Albrecht" uniqKey="Von Brunn A" first="Albrecht" last="Von Brunn">Albrecht Von Brunn</name><affiliation wicri:level="3"><nlm:affiliation>Max-von-Pettenkofer Institute, Ludwig-Maximilians-University Munich and German Center for Infection Research (DZIF), partner site Munich, 80336 Munich, Germany; vonbrunn@mvp.uni-muenchen.de.</nlm:affiliation><country wicri:rule="url">Allemagne</country><wicri:regionArea>Max-von-Pettenkofer Institute, Ludwig-Maximilians-University Munich and German Center for Infection Research (DZIF), partner site Munich, 80336 Munich</wicri:regionArea><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region><settlement type="city">Munich</settlement></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2016">2016</date><idno type="RBID">pubmed:27519799</idno><idno type="pmid">27519799</idno><idno type="doi">10.1073/pnas.1603435113</idno><idno type="wicri:Area/PubMed/Corpus">001004</idno><idno type="wicri:explorRef" wicri:stream="PubMed" 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wicri:level="3"><nlm:affiliation>Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck and German Center for Infection Research, partner site Luebeck, 23538 Luebeck, Germany; Max-von-Pettenkofer Institute, Ludwig-Maximilians-University Munich and German Center for Infection Research (DZIF), partner site Munich, 80336 Munich, Germany;</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck and German Center for Infection Research, partner site Luebeck, 23538 Luebeck, Germany; Max-von-Pettenkofer Institute, Ludwig-Maximilians-University Munich and German Center for Infection Research (DZIF), partner site Munich, 80336 Munich</wicri:regionArea><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region><settlement type="city">Munich</settlement></placeName></affiliation></author><author><name sortKey="Carbajo Lozoya, Javier" sort="Carbajo Lozoya, Javier" uniqKey="Carbajo Lozoya J" first="Javier" last="Carbajo-Lozoya">Javier Carbajo-Lozoya</name><affiliation wicri:level="3"><nlm:affiliation>Max-von-Pettenkofer Institute, Ludwig-Maximilians-University Munich and German Center for Infection Research (DZIF), partner site Munich, 80336 Munich, Germany;</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Max-von-Pettenkofer Institute, Ludwig-Maximilians-University Munich and German Center for Infection Research (DZIF), partner site Munich, 80336 Munich</wicri:regionArea><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region><settlement type="city">Munich</settlement></placeName></affiliation></author><author><name sortKey="Hein, Marco Y" sort="Hein, Marco Y" uniqKey="Hein M" first="Marco Y" last="Hein">Marco Y. Hein</name><affiliation wicri:level="1"><nlm:affiliation>Department of Proteomics and Signal Transduction, Max-Planck Institute of Biochemistry, 82152 Martinsried, Germany;</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Proteomics and Signal Transduction, Max-Planck Institute of Biochemistry, 82152 Martinsried</wicri:regionArea><wicri:noRegion>82152 Martinsried</wicri:noRegion><wicri:noRegion>82152 Martinsried</wicri:noRegion><wicri:noRegion>82152 Martinsried</wicri:noRegion></affiliation></author><author><name sortKey="Muller, Marcel A" sort="Muller, Marcel A" uniqKey="Muller M" first="Marcel A" last="Müller">Marcel A. Müller</name><affiliation wicri:level="3"><nlm:affiliation>Institute of Virology, University of Bonn Medical Centre and German Center for Infection Research, partner site Bonn, 53127 Bonn, Germany;</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Virology, University of Bonn Medical Centre and German Center for Infection Research, partner site Bonn, 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="Deng, Wen" sort="Deng, Wen" uniqKey="Deng W" first="Wen" last="Deng">Wen Deng</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biology and Center for Integrated Protein Science, Ludwig-Maximilians-University Munich, 82152 Planegg-Martinsried, Germany;</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Biology and Center for Integrated Protein Science, Ludwig-Maximilians-University Munich, 82152 Planegg-Martinsried</wicri:regionArea><wicri:noRegion>82152 Planegg-Martinsried</wicri:noRegion><wicri:noRegion>82152 Planegg-Martinsried</wicri:noRegion><wicri:noRegion>82152 Planegg-Martinsried</wicri:noRegion></affiliation></author><author><name sortKey="Lei, Jian" sort="Lei, Jian" uniqKey="Lei J" first="Jian" last="Lei">Jian Lei</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck and German Center for Infection Research, partner site Luebeck, 23538 Luebeck, Germany;</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck and German Center for Infection Research, partner site Luebeck, 23538 Luebeck</wicri:regionArea><wicri:noRegion>23538 Luebeck</wicri:noRegion><wicri:noRegion>23538 Luebeck</wicri:noRegion><wicri:noRegion>23538 Luebeck</wicri:noRegion></affiliation></author><author><name sortKey="Meyer, Benjamin" sort="Meyer, Benjamin" uniqKey="Meyer B" first="Benjamin" last="Meyer">Benjamin Meyer</name><affiliation wicri:level="3"><nlm:affiliation>Institute of Virology, University of Bonn Medical Centre and German Center for Infection Research, partner site Bonn, 53127 Bonn, Germany;</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Virology, University of Bonn Medical Centre and German Center for Infection Research, partner site Bonn, 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="Kusov, Yuri" sort="Kusov, Yuri" uniqKey="Kusov Y" first="Yuri" last="Kusov">Yuri Kusov</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck and German Center for Infection Research, partner site Luebeck, 23538 Luebeck, Germany;</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck and German Center for Infection Research, partner site Luebeck, 23538 Luebeck</wicri:regionArea><wicri:noRegion>23538 Luebeck</wicri:noRegion><wicri:noRegion>23538 Luebeck</wicri:noRegion><wicri:noRegion>23538 Luebeck</wicri:noRegion></affiliation></author><author><name sortKey="Von Brunn, Brigitte" sort="Von Brunn, Brigitte" uniqKey="Von Brunn B" first="Brigitte" last="Von Brunn">Brigitte Von Brunn</name><affiliation wicri:level="3"><nlm:affiliation>Max-von-Pettenkofer Institute, Ludwig-Maximilians-University Munich and German Center for Infection Research (DZIF), partner site Munich, 80336 Munich, Germany;</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Max-von-Pettenkofer Institute, Ludwig-Maximilians-University Munich and German Center for Infection Research (DZIF), partner site Munich, 80336 Munich</wicri:regionArea><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region><settlement type="city">Munich</settlement></placeName></affiliation></author><author><name sortKey="Bairad, Dev Raj" sort="Bairad, Dev Raj" uniqKey="Bairad D" first="Dev Raj" last="Bairad">Dev Raj Bairad</name><affiliation wicri:level="3"><nlm:affiliation>Max-von-Pettenkofer Institute, Ludwig-Maximilians-University Munich and German Center for Infection Research (DZIF), partner site Munich, 80336 Munich, Germany;</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Max-von-Pettenkofer Institute, Ludwig-Maximilians-University Munich and German Center for Infection Research (DZIF), partner site Munich, 80336 Munich</wicri:regionArea><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region><settlement type="city">Munich</settlement></placeName></affiliation></author><author><name sortKey="Hunten, Sabine" sort="Hunten, Sabine" uniqKey="Hunten S" first="Sabine" last="Hünten">Sabine Hünten</name><affiliation wicri:level="3"><nlm:affiliation>Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-University Munich, 80337 Munich, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-University Munich, 80337 Munich</wicri:regionArea><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region><settlement type="city">Munich</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 Centre and German Center for Infection Research, partner site Bonn, 53127 Bonn, Germany;</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Virology, University of Bonn Medical Centre and German Center for Infection Research, partner site Bonn, 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="Hermeking, Heiko" sort="Hermeking, Heiko" uniqKey="Hermeking H" first="Heiko" last="Hermeking">Heiko Hermeking</name><affiliation wicri:level="3"><nlm:affiliation>Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-University Munich, 80337 Munich, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-University Munich, 80337 Munich</wicri:regionArea><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region><settlement type="city">Munich</settlement></placeName></affiliation></author><author><name sortKey="Leonhardt, Heinrich" sort="Leonhardt, Heinrich" uniqKey="Leonhardt H" first="Heinrich" last="Leonhardt">Heinrich Leonhardt</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biology and Center for Integrated Protein Science, Ludwig-Maximilians-University Munich, 82152 Planegg-Martinsried, Germany;</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Biology and Center for Integrated Protein Science, Ludwig-Maximilians-University Munich, 82152 Planegg-Martinsried</wicri:regionArea><wicri:noRegion>82152 Planegg-Martinsried</wicri:noRegion><wicri:noRegion>82152 Planegg-Martinsried</wicri:noRegion><wicri:noRegion>82152 Planegg-Martinsried</wicri:noRegion></affiliation></author><author><name sortKey="Mann, Matthias" sort="Mann, Matthias" uniqKey="Mann M" first="Matthias" last="Mann">Matthias Mann</name><affiliation wicri:level="1"><nlm:affiliation>Department of Proteomics and Signal Transduction, Max-Planck Institute of Biochemistry, 82152 Martinsried, Germany;</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Proteomics and Signal Transduction, Max-Planck Institute of Biochemistry, 82152 Martinsried</wicri:regionArea><wicri:noRegion>82152 Martinsried</wicri:noRegion><wicri:noRegion>82152 Martinsried</wicri:noRegion><wicri:noRegion>82152 Martinsried</wicri:noRegion></affiliation></author><author><name sortKey="Hilgenfeld, Rolf" sort="Hilgenfeld, Rolf" uniqKey="Hilgenfeld R" first="Rolf" last="Hilgenfeld">Rolf Hilgenfeld</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck and German Center for Infection Research, partner site Luebeck, 23538 Luebeck, Germany;</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck and German Center for Infection Research, partner site Luebeck, 23538 Luebeck</wicri:regionArea><wicri:noRegion>23538 Luebeck</wicri:noRegion><wicri:noRegion>23538 Luebeck</wicri:noRegion><wicri:noRegion>23538 Luebeck</wicri:noRegion></affiliation></author><author><name sortKey="Von Brunn, Albrecht" sort="Von Brunn, Albrecht" uniqKey="Von Brunn A" first="Albrecht" last="Von Brunn">Albrecht Von Brunn</name><affiliation wicri:level="3"><nlm:affiliation>Max-von-Pettenkofer Institute, Ludwig-Maximilians-University Munich and German Center for Infection Research (DZIF), partner site Munich, 80336 Munich, Germany; vonbrunn@mvp.uni-muenchen.de.</nlm:affiliation><country wicri:rule="url">Allemagne</country><wicri:regionArea>Max-von-Pettenkofer Institute, Ludwig-Maximilians-University Munich and German Center for Infection Research (DZIF), partner site Munich, 80336 Munich</wicri:regionArea><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region><settlement type="city">Munich</settlement></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="2016" type="published">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Binding Sites (genetics)</term><term>Calcium-Calmodulin-Dependent Protein Kinase Type 2 (genetics)</term><term>Calcium-Calmodulin-Dependent Protein Kinase Type 2 (metabolism)</term><term>Cysteine Endopeptidases (genetics)</term><term>Cysteine Endopeptidases (metabolism)</term><term>Down-Regulation</term><term>Host-Pathogen Interactions</term><term>Humans</term><term>Protein Binding</term><term>SARS Virus (genetics)</term><term>SARS Virus (metabolism)</term><term>SARS Virus (physiology)</term><term>Severe Acute Respiratory Syndrome (genetics)</term><term>Severe Acute Respiratory Syndrome (metabolism)</term><term>Severe Acute Respiratory Syndrome (virology)</term><term>Tumor Suppressor Protein p53 (metabolism)</term><term>Ubiquitin-Protein Ligases (genetics)</term><term>Ubiquitin-Protein Ligases (metabolism)</term><term>Ubiquitination</term><term>Viral Nonstructural Proteins (genetics)</term><term>Viral Nonstructural Proteins (metabolism)</term><term>Viral Proteins (genetics)</term><term>Viral Proteins (metabolism)</term><term>Virus Replication (genetics)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Calcium-Calmodulin-Dependent Protein Kinase Type 2 (génétique)</term><term>Calcium-Calmodulin-Dependent Protein Kinase Type 2 (métabolisme)</term><term>Cysteine endopeptidases (génétique)</term><term>Cysteine endopeptidases (métabolisme)</term><term>Humains</term><term>Interactions hôte-pathogène</term><term>Liaison aux protéines</term><term>Protéine p53 suppresseur de tumeur (métabolisme)</term><term>Protéines virales (génétique)</term><term>Protéines virales (métabolisme)</term><term>Protéines virales non structurales (génétique)</term><term>Protéines virales non structurales (métabolisme)</term><term>Régulation négative</term><term>Réplication virale (génétique)</term><term>Sites de fixation (génétique)</term><term>Syndrome respiratoire aigu sévère (génétique)</term><term>Syndrome respiratoire aigu sévère (métabolisme)</term><term>Syndrome respiratoire aigu sévère (virologie)</term><term>Ubiquitin-protein ligases (génétique)</term><term>Ubiquitin-protein ligases (métabolisme)</term><term>Ubiquitinylation</term><term>Virus du SRAS (génétique)</term><term>Virus du SRAS (métabolisme)</term><term>Virus du SRAS (physiologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Calcium-Calmodulin-Dependent Protein Kinase Type 2</term><term>Cysteine Endopeptidases</term><term>Ubiquitin-Protein Ligases</term><term>Viral Nonstructural Proteins</term><term>Viral Proteins</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Binding Sites</term><term>SARS Virus</term><term>Severe Acute Respiratory Syndrome</term><term>Virus Replication</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Calcium-Calmodulin-Dependent Protein Kinase Type 2</term><term>Cysteine endopeptidases</term><term>Protéines virales</term><term>Protéines virales non structurales</term><term>Réplication virale</term><term>Sites de fixation</term><term>Syndrome respiratoire aigu sévère</term><term>Ubiquitin-protein ligases</term><term>Virus du SRAS</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Calcium-Calmodulin-Dependent Protein Kinase Type 2</term><term>Cysteine Endopeptidases</term><term>SARS Virus</term><term>Severe Acute Respiratory Syndrome</term><term>Tumor Suppressor Protein p53</term><term>Ubiquitin-Protein Ligases</term><term>Viral Nonstructural Proteins</term><term>Viral Proteins</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Calcium-Calmodulin-Dependent Protein Kinase Type 2</term><term>Cysteine endopeptidases</term><term>Protéine p53 suppresseur de tumeur</term><term>Protéines virales</term><term>Protéines virales non structurales</term><term>Syndrome respiratoire aigu sévère</term><term>Ubiquitin-protein ligases</term><term>Virus du SRAS</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Virus du SRAS</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="virologie" xml:lang="fr"><term>Syndrome respiratoire aigu sévère</term></keywords><keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>Severe Acute Respiratory Syndrome</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Down-Regulation</term><term>Host-Pathogen Interactions</term><term>Humans</term><term>Protein Binding</term><term>Ubiquitination</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Humains</term><term>Interactions hôte-pathogène</term><term>Liaison aux protéines</term><term>Régulation négative</term><term>Ubiquitinylation</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Highly pathogenic severe acute respiratory syndrome coronavirus (SARS-CoV) has developed strategies to inhibit host immune recognition. We identify cellular E3 ubiquitin ligase ring-finger and CHY zinc-finger domain-containing 1 (RCHY1) as an interacting partner of the viral SARS-unique domain (SUD) and papain-like protease (PL(pro)), and, as a consequence, the involvement of cellular p53 as antagonist of coronaviral replication. Residues 95-144 of RCHY1 and 389-652 of SUD (SUD-NM) subdomains are crucial for interaction. Association with SUD increases the stability of RCHY1 and augments RCHY1-mediated ubiquitination as well as degradation of p53. The calcium/calmodulin-dependent protein kinase II delta (CAMK2D), which normally influences RCHY1 stability by phosphorylation, also binds to SUD. In vivo phosphorylation shows that SUD does not regulate phosphorylation of RCHY1 via CAMK2D. Similarly to SUD, the PL(pro)s from SARS-CoV, MERS-CoV, and HCoV-NL63 physically interact with and stabilize RCHY1, and thus trigger degradation of endogenous p53. The SARS-CoV papain-like protease is encoded next to SUD within nonstructural protein 3. A SUD-PL(pro) fusion interacts with RCHY1 more intensively and causes stronger p53 degradation than SARS-CoV PL(pro) alone. We show that p53 inhibits replication of infectious SARS-CoV as well as of replicons and human coronavirus NL63. Hence, human coronaviruses antagonize the viral inhibitor p53 via stabilizing RCHY1 and promoting RCHY1-mediated p53 degradation. SUD functions as an enhancer to strengthen interaction between RCHY1 and nonstructural protein 3, leading to a further increase in in p53 degradation. The significance of these findings is that down-regulation of p53 as a major player in antiviral innate immunity provides a long-sought explanation for delayed activities of respective genes.</div></front></TEI><affiliations><list><country><li>Allemagne</li></country><region><li>Bavière</li><li>District de Cologne</li><li>District de Haute-Bavière</li><li>Rhénanie-du-Nord-Westphalie</li></region><settlement><li>Bonn</li><li>Munich</li></settlement></list><tree><country name="Allemagne"><region name="Bavière"><name sortKey="Ma Lauer, Yue" sort="Ma Lauer, Yue" uniqKey="Ma Lauer Y" first="Yue" last="Ma-Lauer">Yue Ma-Lauer</name></region><name sortKey="Bairad, Dev Raj" sort="Bairad, Dev Raj" uniqKey="Bairad D" first="Dev Raj" last="Bairad">Dev Raj Bairad</name><name sortKey="Carbajo Lozoya, Javier" sort="Carbajo Lozoya, Javier" uniqKey="Carbajo Lozoya J" first="Javier" last="Carbajo-Lozoya">Javier Carbajo-Lozoya</name><name sortKey="Deng, Wen" sort="Deng, Wen" uniqKey="Deng W" first="Wen" last="Deng">Wen Deng</name><name sortKey="Drosten, Christian" sort="Drosten, Christian" uniqKey="Drosten C" first="Christian" last="Drosten">Christian Drosten</name><name sortKey="Hein, Marco Y" sort="Hein, Marco Y" uniqKey="Hein M" first="Marco Y" last="Hein">Marco Y. Hein</name><name sortKey="Hermeking, Heiko" sort="Hermeking, Heiko" uniqKey="Hermeking H" first="Heiko" last="Hermeking">Heiko Hermeking</name><name sortKey="Hilgenfeld, Rolf" sort="Hilgenfeld, Rolf" uniqKey="Hilgenfeld R" first="Rolf" last="Hilgenfeld">Rolf Hilgenfeld</name><name sortKey="Hunten, Sabine" sort="Hunten, Sabine" uniqKey="Hunten S" first="Sabine" last="Hünten">Sabine Hünten</name><name sortKey="Kusov, Yuri" sort="Kusov, Yuri" uniqKey="Kusov Y" first="Yuri" last="Kusov">Yuri Kusov</name><name sortKey="Lei, Jian" sort="Lei, Jian" uniqKey="Lei J" first="Jian" last="Lei">Jian Lei</name><name sortKey="Leonhardt, Heinrich" sort="Leonhardt, Heinrich" uniqKey="Leonhardt H" first="Heinrich" last="Leonhardt">Heinrich Leonhardt</name><name sortKey="Mann, Matthias" sort="Mann, Matthias" uniqKey="Mann M" first="Matthias" last="Mann">Matthias Mann</name><name sortKey="Meyer, Benjamin" sort="Meyer, Benjamin" uniqKey="Meyer B" first="Benjamin" last="Meyer">Benjamin Meyer</name><name sortKey="Muller, Marcel A" sort="Muller, Marcel A" uniqKey="Muller M" first="Marcel A" last="Müller">Marcel A. Müller</name><name sortKey="Von Brunn, Albrecht" sort="Von Brunn, Albrecht" uniqKey="Von Brunn A" first="Albrecht" last="Von Brunn">Albrecht Von Brunn</name><name sortKey="Von Brunn, Brigitte" sort="Von Brunn, Brigitte" uniqKey="Von Brunn B" first="Brigitte" last="Von Brunn">Brigitte Von Brunn</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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