Mutations in DNA Binding and Transactivation Domains Affect the Dynamics of Parvovirus NS1 Protein

Niskanen, Einari A.; Kalliolinna, Olli; Ihalainen, Teemu O.; Häkkinen, Milla; Vihinen‐Ranta, Maija

doi:10.1128/jvi.01678-13

Cited by 25 publications

(23 citation statements)

References 58 publications

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“…There are also limited studies on the NS1 protein, based only on evaluations of its functions [66,67,68] and on the potential location of its functional domains [10,22,23]. Changes in specific residues of NS1 CPV sequence [27] or affecting functional domains in others Carnivore protoparvovirus 1 such as mink enteritis parvovirus [69] were hypothesized as potentially affecting the functions of this protein.…”

Section: Discussionmentioning

confidence: 99%

“…Among encoded structural proteins, VP2 is the major capsid protein, represents the main determinant of host range, and is subject to antibody-mediated selection [20,21]. On the other hand, the nonstructural proteins NS1 and NS2 are essential for viral replication, DNA packaging, cytotoxicity, and pathogenicity [22,23,24]. Due to the involvement of the VP2 capsid protein in host switch and due to its fast evolutionary rate, most studies on CPV and FPLV focused their attention on the VP2 gene and on the structural analysis of the encoded protein.…”

Section: Introductionmentioning

confidence: 99%

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Molecular Characterization and Evolutionary Analyses of Carnivore Protoparvovirus 1 NS1 Gene

Mira

Canuti

Purpari

et al. 2019

Viruses

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Carnivore protoparvovirus 1 is the etiological agent of a severe disease of terrestrial carnivores. This unique specie encompasses canine parvovirus type 2 (CPV-2) and feline panleukopenia virus (FPLV). Studies widely analyzed the main capsid protein (VP2), but limited information is available on the nonstructural genes (NS1/NS2). This paper analyzed the NS1 gene sequence of FPLV and CPV strains collected in Italy in 2009–2017, along with worldwide related sequences. Differently from VP2, only one NS1 amino-acid residue (248) clearly and constantly distinguished FPLV from CPV-2, while five possible convergent amino-acid changes were observed that may affect the functional domains of the NS1. Some synonymous mutation in NS1 were non-synonymous in NS2 and vice versa. No evidence for recombination between the two lineages was found, and the predominance of negative selection pressure on NS1 proteins was observed, with low and no overlap between the two lineages in negatively and positively selected codons, respectively. More sites were under selection in the CPV-2 lineage. NS1 phylogenetic analysis showed divergent evolution between FPLV and CPV, and strains were clustered mostly by country and year of detection. We highlight the importance of obtaining the NS1/NS2 coding sequence in molecular epidemiology investigations.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Molecular Characterization and Evolutionary Analyses of Carnivore Protoparvovirus 1 NS1 Gene

Mira

Canuti

Purpari

et al. 2019

Viruses

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“…NS1 is a multifunctional nuclear phosphoprotein responsible for viral replication, cellular transcription and cell death inducing apoptosis (Gupta et al, 2016;Saxena et al, 2013). Only recently some of CPV NS1 amino acids were associated to specific functions (Niskanen et al, 2010(Niskanen et al, , 2013. In order to contribute to future studies on this gene, we provided a complete genome NS1 sequencing for a number of CPV strains.…”

Section: Discussionmentioning

confidence: 99%

Molecular typing of a novel canine parvovirus type 2a mutant circulating in Italy

Mira

Dowgier

Purpari

et al. 2018

Infection, Genetics and Evolution

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Canine parvovirus (CPV) is the etiological agent of a severe viral disease of dogs. After its emergence in late 1970s, the CPV original type (CPV-2) was rapidly and totally replaced by three antigenic variants named CPV-2a, CPV-2b and CPV-2c. CPV has an evolutionary rate nearest to those of RNA viruses, with consequences on disease diagnosis and epidemiology. This paper reports the molecular characterization of eight CPV-2a strains collected from dogs in Italy in 2016-2017. Genetic analysis was conducted on a CPV genomic region encompassing both open reading frames (ORFs) encoding for nonstructural (NS1-NS2) and structural proteins (VP1-VP2). Sequence analysis indicates new and unreported sequence changes, mainly affecting the VP2 gene, which included the mutation Tyr324Leu. This study represents the first evidence of a new CPV-2a mutant (VP2 324Leu) and illustrates the importance of a continuous molecular survey in order to obtain more information on effective spread of new CPV mutants.

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“…Here, our PLA studies revealed that CPV NS1 was located in close proximity to H3K27ac in the enlarged APAR bodies. Our earlier studies indicated that CPV NS1 has two distinct binding sites in the viral genome (53,54,57). It is tempting to speculate that NS1 is involved in the histone acetylation of viral P4 and P38 promoters by recruiting host proteins with acetyltransferase activity.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, our analysis demonstrated that H3K27ac was located in close proximity to the viral NS1 protein in the APAR bodies. This interaction likely is caused by the accumulation of NS1 on viral genomes because of its involvement in transcription and replication (52)(53)(54). NS1 of autonomous parvoviruses not only controls the viral activities but also regulates host gene expression through histone acetylation in cancer cells by recruiting innate proteins with HAT activity (55,56).…”

Section: Discussionmentioning

confidence: 99%

Promoter-Targeted Histone Acetylation of Chromatinized Parvoviral Genome Is Essential for the Progress of Infection

Mäntylä

Salokas

Oittinen

et al. 2016

J Virol

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The association of host histones with parvoviral DNA is poorly understood. We analyzed the chromatinization and histone acetylation of canine parvovirus DNA during infection by confocal imaging and in situ proximity ligation assay combined with chromatin immunoprecipitation and high-throughput sequencing. We found that during late infection, parvovirus replication bodies were rich in histones bearing modifications characteristic of transcriptionally active chromatin, i.e., histone H3 lysine 27 acetylation (H3K27ac). H3K27ac, in particular, was located in close proximity to the viral DNA-binding protein NS1. Importantly, our results show for the first time that in the chromatinized parvoviral genome, the two viral promoters in particular were rich in H3K27ac. Histone acetyltransferase (HAT) inhibitors efficiently interfered with the expression of viral proteins and infection progress. Altogether, our data suggest that the acetylation of histones on parvoviral DNA is essential for viral gene expression and the completion of the viral life cycle. IMPORTANCEViral DNA introduced into cell nuclei is exposed to cellular responses to foreign DNA, including chromatinization and epigenetic silencing, both of which determine the outcome of infection. How the incoming parvovirus resists cellular epigenetic downregulation of its genes is not understood. Here, the critical role of epigenetic modifications in the regulation of parvovirus infection was demonstrated. We showed for the first time that a successful parvovirus infection is characterized by the deposition of nucleosomes with active histone acetylation on the viral promoter areas. The results provide new insights into the regulation of parvoviral gene expression, which is an important aspect of the development of parvovirus-based virotherapy. N uclear chromatin is composed of DNA and histone proteins (1). The histone proteins assemble DNA into nucleosomes, the composition and spacing of which contribute to higher-order chromatin packing. The chromatin is organized into regions of less-condensed actively transcribed chromatin (euchromatin) and highly condensed transcriptionally repressed chromatin (heterochromatin). Epigenetic modifications of histone proteins have been shown to correlate with the spatial distribution of active and repressed chromatin (2, 3). The acetylation of lysine 9 or 27 of histone H3 (H3K9ac and H3K27ac, respectively) and trimethylation of lysine 4 (H3K4me3) correlate with transcriptional activity, while repressed chromatin is characterized by, e.g., trimethylation or dimethylation of the same H3 lysine residues (H3K9me3 and H3K27me3 as well as H3K9me2 and H3K27me2) (4-8).Foreign DNA introduced into mammalian cells can be recognized as a threat by the host cell. The cellular responses to the foreign DNA, such as viral DNA, include the chromatinization of the entering DNA, leading to its transcriptional silencing (9-11). How viruses resist cellular chromatinization and silencing is known for only a few viruses (9, 12, 13). These include h...

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Mutations in DNA Binding and Transactivation Domains Affect the Dynamics of Parvovirus NS1 Protein

Cited by 25 publications

References 58 publications

Molecular Characterization and Evolutionary Analyses of Carnivore Protoparvovirus 1 NS1 Gene

Molecular Characterization and Evolutionary Analyses of Carnivore Protoparvovirus 1 NS1 Gene

Molecular typing of a novel canine parvovirus type 2a mutant circulating in Italy

Promoter-Targeted Histone Acetylation of Chromatinized Parvoviral Genome Is Essential for the Progress of Infection

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