The C-terminal 18 Amino Acid Region of Dengue Virus NS5 Regulates its Subcellular Localization and Contains a Conserved Arginine Residue Essential for Infectious Virus Production
Identifieur interne : 001638 ( Main/Exploration ); précédent : 001637; suivant : 001639The C-terminal 18 Amino Acid Region of Dengue Virus NS5 Regulates its Subcellular Localization and Contains a Conserved Arginine Residue Essential for Infectious Virus Production
Auteurs : Moon Y. F. Tay [Singapour] ; Kate Smith [Australie] ; Ivan H. W. Ng [Singapour] ; Kitti W. K. Chan [Singapour] ; Yongqian Zhao [Singapour] ; Eng Eong Ooi [Singapour] ; Julien Lescar [Singapour, France] ; Dahai Luo [Singapour] ; David A. Jans [Australie] ; Jade K. Forwood [Australie] ; Subhash G. Vasudevan [Singapour]Source :
- PLoS Pathogens [ 1553-7366 ] ; 2016.
Descripteurs français
- KwdFr :
- Animaux, Cricetinae, Domaines protéiques, Humains, Lignée cellulaire, Mutation faux-sens, Noyau de la cellule (métabolisme), Noyau de la cellule (virologie), Protéines virales non structurales (génétique), Protéines virales non structurales (métabolisme), Réplication virale, Signaux de localisation nucléaire (génétique), Signaux de localisation nucléaire (métabolisme), Substitution d'acide aminé, Transport nucléaire actif, Virus de la dengue (physiologie).
- MESH :
- génétique : Protéines virales non structurales, Signaux de localisation nucléaire.
- métabolisme : Noyau de la cellule, Protéines virales non structurales, Signaux de localisation nucléaire.
- physiologie : Virus de la dengue.
- virologie : Noyau de la cellule.
- Animaux, Cricetinae, Domaines protéiques, Humains, Lignée cellulaire, Mutation faux-sens, Réplication virale, Substitution d'acide aminé, Transport nucléaire actif.
English descriptors
- KwdEn :
- Active Transport, Cell Nucleus, Amino Acid Substitution, Animals, Cell Line, Cell Nucleus (metabolism), Cell Nucleus (virology), Cricetinae, Dengue Virus (physiology), Humans, Mutation, Missense, Nuclear Localization Signals (genetics), Nuclear Localization Signals (metabolism), Protein Domains, Viral Nonstructural Proteins (genetics), Viral Nonstructural Proteins (metabolism), Virus Replication.
- MESH :
- chemical , genetics : Nuclear Localization Signals, Viral Nonstructural Proteins.
- metabolism : Cell Nucleus, Nuclear Localization Signals, Viral Nonstructural Proteins.
- physiology : Dengue Virus.
- virology : Cell Nucleus.
- Active Transport, Cell Nucleus, Amino Acid Substitution, Animals, Cell Line, Cricetinae, Humans, Mutation, Missense, Protein Domains, Virus Replication.
Abstract
Dengue virus NS5 is the most highly conserved amongst the viral non-structural proteins and is responsible for capping, methylation and replication of the flavivirus RNA genome. Interactions of NS5 with host proteins also modulate host immune responses. Although replication occurs in the cytoplasm, an unusual characteristic of DENV2 NS5 is that it localizes to the nucleus during infection with no clear role in replication or pathogenesis. We examined NS5 of DENV1 and 2, which exhibit the most prominent difference in nuclear localization, employing a combination of functional and structural analyses. Extensive gene swapping between DENV1 and 2 NS5 identified that the C-terminal 18 residues (Cter18) alone was sufficient to direct the protein to the cytoplasm or nucleus, respectively. The low micromolar binding affinity between NS5 Cter18 and the nuclear import receptor importin-alpha (Impα), allowed their molecular complex to be purified, crystallised and visualized at 2.2 Å resolution using x-ray crystallography. Structure-guided mutational analysis of this region in GFP-NS5 clones of DENV1 or 2 and in a DENV2 infectious clone reveal residues important for NS5 subcellular localization. Notably, the
Url:
DOI: 10.1371/journal.ppat.1005886
PubMed: 27622521
PubMed Central: 5021334
Affiliations:
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Centre Hospitalier Universitaire Pitié-Salpêtrière, Faculté de Médecine Pierre et Marie Curie, Paris, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>UPMC UMRS CR7—CNRS ERL 8255-INSERM U1135 Centre d’Immunologie et des Maladies Infectieuses. 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F." last="Tay">Moon Y. F. Tay</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Program in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore</addr-line></nlm:aff><country xml:lang="fr">Singapour</country><wicri:regionArea>Program in Emerging Infectious Diseases, Duke-NUS Medical School</wicri:regionArea><wicri:noRegion>Duke-NUS Medical School</wicri:noRegion></affiliation></author><author><name sortKey="Smith, Kate" sort="Smith, Kate" uniqKey="Smith K" first="Kate" last="Smith">Kate Smith</name><affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, New South Wales, Australia</addr-line></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, New South Wales</wicri:regionArea><wicri:noRegion>New South Wales</wicri:noRegion></affiliation></author><author><name sortKey="Ng, Ivan H W" sort="Ng, Ivan H W" uniqKey="Ng I" first="Ivan H. W." last="Ng">Ivan H. W. Ng</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Program in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore</addr-line></nlm:aff><country xml:lang="fr">Singapour</country><wicri:regionArea>Program in Emerging Infectious Diseases, Duke-NUS Medical School</wicri:regionArea><wicri:noRegion>Duke-NUS Medical School</wicri:noRegion></affiliation></author><author><name sortKey="Chan, Kitti W K" sort="Chan, Kitti W K" uniqKey="Chan K" first="Kitti W. K." last="Chan">Kitti W. K. Chan</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Program in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore</addr-line></nlm:aff><country xml:lang="fr">Singapour</country><wicri:regionArea>Program in Emerging Infectious Diseases, Duke-NUS Medical School</wicri:regionArea><wicri:noRegion>Duke-NUS Medical School</wicri:noRegion></affiliation><affiliation wicri:level="4"><nlm:aff id="aff003"><addr-line>Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore</addr-line></nlm:aff><country xml:lang="fr">Singapour</country><wicri:regionArea>Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore</wicri:regionArea><orgName type="university">Université nationale de Singapour</orgName></affiliation></author><author><name sortKey="Zhao, Yongqian" sort="Zhao, Yongqian" uniqKey="Zhao Y" first="Yongqian" last="Zhao">Yongqian Zhao</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Program in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore</addr-line></nlm:aff><country xml:lang="fr">Singapour</country><wicri:regionArea>Program in Emerging Infectious Diseases, Duke-NUS Medical School</wicri:regionArea><wicri:noRegion>Duke-NUS Medical School</wicri:noRegion></affiliation></author><author><name sortKey="Ooi, Eng Eong" sort="Ooi, Eng Eong" uniqKey="Ooi E" first="Eng Eong" last="Ooi">Eng Eong Ooi</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Program in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore</addr-line></nlm:aff><country xml:lang="fr">Singapour</country><wicri:regionArea>Program in Emerging Infectious Diseases, Duke-NUS Medical School</wicri:regionArea><wicri:noRegion>Duke-NUS Medical School</wicri:noRegion></affiliation><affiliation wicri:level="4"><nlm:aff id="aff003"><addr-line>Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore</addr-line></nlm:aff><country xml:lang="fr">Singapour</country><wicri:regionArea>Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore</wicri:regionArea><orgName type="university">Université nationale de Singapour</orgName></affiliation></author><author><name sortKey="Lescar, Julien" sort="Lescar, Julien" uniqKey="Lescar J" first="Julien" last="Lescar">Julien Lescar</name><affiliation wicri:level="1"><nlm:aff id="aff004"><addr-line>School of Biological Sciences, Nanyang Technological University, Singapore</addr-line></nlm:aff><country xml:lang="fr">Singapour</country><wicri:regionArea>School of Biological Sciences, Nanyang Technological University</wicri:regionArea><wicri:noRegion>Nanyang Technological University</wicri:noRegion></affiliation><affiliation wicri:level="3"><nlm:aff id="aff005"><addr-line>UPMC UMRS CR7—CNRS ERL 8255-INSERM U1135 Centre d’Immunologie et des Maladies Infectieuses. Centre Hospitalier Universitaire Pitié-Salpêtrière, Faculté de Médecine Pierre et Marie Curie, Paris, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>UPMC UMRS CR7—CNRS ERL 8255-INSERM U1135 Centre d’Immunologie et des Maladies Infectieuses. Centre Hospitalier Universitaire Pitié-Salpêtrière, Faculté de Médecine Pierre et Marie Curie, Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Luo, Dahai" sort="Luo, Dahai" uniqKey="Luo D" first="Dahai" last="Luo">Dahai Luo</name><affiliation wicri:level="1"><nlm:aff id="aff006"><addr-line>Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore</addr-line></nlm:aff><country xml:lang="fr">Singapour</country><wicri:regionArea>Lee Kong Chian School of Medicine, Nanyang Technological University</wicri:regionArea><wicri:noRegion>Nanyang Technological University</wicri:noRegion></affiliation></author><author><name sortKey="Jans, David A" sort="Jans, David A" uniqKey="Jans D" first="David A." last="Jans">David A. Jans</name><affiliation wicri:level="1"><nlm:aff id="aff007"><addr-line>Nuclear Signalling Laboratory, Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Victoria, Australia</addr-line></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Nuclear Signalling Laboratory, Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Victoria</wicri:regionArea><wicri:noRegion>Victoria</wicri:noRegion></affiliation></author><author><name sortKey="Forwood, Jade K" sort="Forwood, Jade K" uniqKey="Forwood J" first="Jade K." last="Forwood">Jade K. Forwood</name><affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, New South Wales, Australia</addr-line></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, New South Wales</wicri:regionArea><wicri:noRegion>New South Wales</wicri:noRegion></affiliation></author><author><name sortKey="Vasudevan, Subhash G" sort="Vasudevan, Subhash G" uniqKey="Vasudevan S" first="Subhash G." last="Vasudevan">Subhash G. Vasudevan</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Program in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore</addr-line></nlm:aff><country xml:lang="fr">Singapour</country><wicri:regionArea>Program in Emerging Infectious Diseases, Duke-NUS Medical School</wicri:regionArea><wicri:noRegion>Duke-NUS Medical School</wicri:noRegion></affiliation><affiliation wicri:level="4"><nlm:aff id="aff003"><addr-line>Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore</addr-line></nlm:aff><country xml:lang="fr">Singapour</country><wicri:regionArea>Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore</wicri:regionArea><orgName type="university">Université nationale de Singapour</orgName></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="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Active Transport, Cell Nucleus</term><term>Amino Acid Substitution</term><term>Animals</term><term>Cell Line</term><term>Cell Nucleus (metabolism)</term><term>Cell Nucleus (virology)</term><term>Cricetinae</term><term>Dengue Virus (physiology)</term><term>Humans</term><term>Mutation, Missense</term><term>Nuclear Localization Signals (genetics)</term><term>Nuclear Localization Signals (metabolism)</term><term>Protein Domains</term><term>Viral Nonstructural Proteins (genetics)</term><term>Viral Nonstructural Proteins (metabolism)</term><term>Virus Replication</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term><term>Cricetinae</term><term>Domaines protéiques</term><term>Humains</term><term>Lignée cellulaire</term><term>Mutation faux-sens</term><term>Noyau de la cellule (métabolisme)</term><term>Noyau de la cellule (virologie)</term><term>Protéines virales non structurales (génétique)</term><term>Protéines virales non structurales (métabolisme)</term><term>Réplication virale</term><term>Signaux de localisation nucléaire (génétique)</term><term>Signaux de localisation nucléaire (métabolisme)</term><term>Substitution d'acide aminé</term><term>Transport nucléaire actif</term><term>Virus de la dengue (physiologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Nuclear Localization Signals</term><term>Viral Nonstructural Proteins</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Protéines virales non structurales</term><term>Signaux de localisation nucléaire</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Cell Nucleus</term><term>Nuclear Localization Signals</term><term>Viral Nonstructural Proteins</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Noyau de la cellule</term><term>Protéines virales non structurales</term><term>Signaux de localisation nucléaire</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Virus de la dengue</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Dengue Virus</term></keywords><keywords scheme="MESH" qualifier="virologie" xml:lang="fr"><term>Noyau de la cellule</term></keywords><keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>Cell Nucleus</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Active Transport, Cell Nucleus</term><term>Amino Acid Substitution</term><term>Animals</term><term>Cell Line</term><term>Cricetinae</term><term>Humans</term><term>Mutation, Missense</term><term>Protein Domains</term><term>Virus Replication</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Cricetinae</term><term>Domaines protéiques</term><term>Humains</term><term>Lignée cellulaire</term><term>Mutation faux-sens</term><term>Réplication virale</term><term>Substitution d'acide aminé</term><term>Transport nucléaire actif</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Dengue virus NS5 is the most highly conserved amongst the viral non-structural proteins and is responsible for capping, methylation and replication of the flavivirus RNA genome. Interactions of NS5 with host proteins also modulate host immune responses. Although replication occurs in the cytoplasm, an unusual characteristic of DENV2 NS5 is that it localizes to the nucleus during infection with no clear role in replication or pathogenesis. We examined NS5 of DENV1 and 2, which exhibit the most prominent difference in nuclear localization, employing a combination of functional and structural analyses. Extensive gene swapping between DENV1 and 2 NS5 identified that the C-terminal 18 residues (Cter<sub>18</sub>) alone was sufficient to direct the protein to the cytoplasm or nucleus, respectively. The low micromolar binding affinity between NS5 Cter<sub>18</sub> and the nuclear import receptor importin-alpha (Impα), allowed their molecular complex to be purified, crystallised and visualized at 2.2 Å resolution using x-ray crystallography. Structure-guided mutational analysis of this region in GFP-NS5 clones of DENV1 or 2 and in a DENV2 infectious clone reveal residues important for NS5 subcellular localization. Notably, the <italic>trans</italic> conformation adopted by Pro-884 allows proper presentation for binding Impα and mutating this proline to Thr, as present in DENV1 NS5, results in mislocalizaion of NS5 to the cytoplasm without compromising virus fitness. In contrast, a single mutation to alanine at NS5 position R888, a residue conserved in all flaviviruses, resulted in a completely non-viable virus, and the R888K mutation led to a severely attenuated phentoype, even though NS5 was located in the nucleus. R888 forms a hydrogen bond with Y838 that is also conserved in all flaviviruses. Our data suggests an evolutionarily conserved function for NS5 Cter<sub>18</sub>, possibly in RNA interactions that are critical for replication, that is independent of its role in subcellular localization.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Bhatt, S" uniqKey="Bhatt S">S Bhatt</name></author><author><name sortKey="Gething, Pw" uniqKey="Gething P">PW Gething</name></author><author><name sortKey="Brady, Oj" uniqKey="Brady O">OJ Brady</name></author><author><name sortKey="Messina, Jp" uniqKey="Messina J">JP Messina</name></author><author><name sortKey="Farlow, Aw" uniqKey="Farlow A">AW Farlow</name></author><author><name sortKey="Moyes, Cl" uniqKey="Moyes C">CL Moyes</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gubler, Dj" uniqKey="Gubler D">DJ Gubler</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Halstead, Sb" uniqKey="Halstead S">SB 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Chang</name></author><author><name sortKey="Kobe, B" uniqKey="Kobe B">B Kobe</name></author><author><name sortKey="Fontes, Mr" uniqKey="Fontes M">MR Fontes</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mynott, Av" uniqKey="Mynott A">AV Mynott</name></author><author><name sortKey="Harrop, Sj" uniqKey="Harrop S">SJ Harrop</name></author><author><name sortKey="Brown, Lj" uniqKey="Brown L">LJ Brown</name></author><author><name sortKey="Breit, Sn" uniqKey="Breit S">SN Breit</name></author><author><name sortKey="Kobe, B" uniqKey="Kobe B">B Kobe</name></author><author><name sortKey="Curmi, Pm" uniqKey="Curmi P">PM Curmi</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>Australie</li><li>France</li><li>Singapour</li></country><region><li>Île-de-France</li></region><settlement><li>Paris</li></settlement><orgName><li>Université nationale de Singapour</li></orgName></list><tree><country name="Singapour"><noRegion><name sortKey="Tay, Moon Y F" sort="Tay, Moon Y F" uniqKey="Tay M" first="Moon Y. F." last="Tay">Moon Y. F. Tay</name></noRegion><name sortKey="Chan, Kitti W K" sort="Chan, Kitti W K" uniqKey="Chan K" first="Kitti W. K." last="Chan">Kitti W. K. Chan</name><name sortKey="Chan, Kitti W K" sort="Chan, Kitti W K" uniqKey="Chan K" first="Kitti W. K." last="Chan">Kitti W. K. Chan</name><name sortKey="Lescar, Julien" sort="Lescar, Julien" uniqKey="Lescar J" first="Julien" last="Lescar">Julien Lescar</name><name sortKey="Luo, Dahai" sort="Luo, Dahai" uniqKey="Luo D" first="Dahai" last="Luo">Dahai Luo</name><name sortKey="Ng, Ivan H W" sort="Ng, Ivan H W" uniqKey="Ng I" first="Ivan H. W." last="Ng">Ivan H. W. Ng</name><name sortKey="Ooi, Eng Eong" sort="Ooi, Eng Eong" uniqKey="Ooi E" first="Eng Eong" last="Ooi">Eng Eong Ooi</name><name sortKey="Ooi, Eng Eong" sort="Ooi, Eng Eong" uniqKey="Ooi E" first="Eng Eong" last="Ooi">Eng Eong Ooi</name><name sortKey="Vasudevan, Subhash G" sort="Vasudevan, Subhash G" uniqKey="Vasudevan S" first="Subhash G." last="Vasudevan">Subhash G. Vasudevan</name><name sortKey="Vasudevan, Subhash G" sort="Vasudevan, Subhash G" uniqKey="Vasudevan S" first="Subhash G." last="Vasudevan">Subhash G. Vasudevan</name><name sortKey="Zhao, Yongqian" sort="Zhao, Yongqian" uniqKey="Zhao Y" first="Yongqian" last="Zhao">Yongqian Zhao</name></country><country name="Australie"><noRegion><name sortKey="Smith, Kate" sort="Smith, Kate" uniqKey="Smith K" first="Kate" last="Smith">Kate Smith</name></noRegion><name sortKey="Forwood, Jade K" sort="Forwood, Jade K" uniqKey="Forwood J" first="Jade K." last="Forwood">Jade K. Forwood</name><name sortKey="Jans, David A" sort="Jans, David A" uniqKey="Jans D" first="David A." last="Jans">David A. Jans</name></country><country name="France"><region name="Île-de-France"><name sortKey="Lescar, Julien" sort="Lescar, Julien" uniqKey="Lescar J" first="Julien" last="Lescar">Julien Lescar</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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