AustralieFrV1, PubMed, Curation, bibRecord, 001923

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 : 001923 ( PubMed/Curation ); précédent : 001922; suivant : 001924

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.

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] ; Dahai Luo [Singapour] ; David A. Jans [Australie] ; Jade K. Forwood [Australie] ; Subhash G. Vasudevan [Singapour]

Source :

PLoS pathogens [ 1553-7374 ] ; 2016.

RBID : pubmed:27622521

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 trans 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 Cter18, possibly in RNA interactions that are critical for replication, that is independent of its role in subcellular localization.

DOI: 10.1371/journal.ppat.1005886
PubMed: 27622521

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<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>
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<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>
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<term>Protéines virales non structurales</term>
<term>Signaux de localisation nucléaire</term>
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<front><div type="abstract" xml:lang="en">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 trans 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 Cter18, possibly in RNA interactions that are critical for replication, that is independent of its role in subcellular localization.</div>
</front>
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<ArticleTitle>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.</ArticleTitle>
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<Abstract><AbstractText>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 trans 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 Cter18, possibly in RNA interactions that are critical for replication, that is independent of its role in subcellular localization.</AbstractText>
</Abstract>
<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Tay</LastName>
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<Initials>K</Initials>
<AffiliationInfo><Affiliation>School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, New South Wales, Australia.</Affiliation>
</AffiliationInfo>
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<Author ValidYN="Y"><LastName>Ng</LastName>
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<Initials>KW</Initials>
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<AffiliationInfo><Affiliation>Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.</Affiliation>
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<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName>
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   |texte=   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.
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	Serveur d'exploration sur les relations entre la France et l'Australie
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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.

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.

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