Roles of Cellular Transcription Factors in VZV Replication

Ruyechan, William T.

doi:10.1007/82_2010_42

Cited by 12 publications

(17 citation statements)

References 112 publications

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“…For example, the transcription factor specificity protein 1 (Sp1) increases the recruitment of IE62 to viral promoters 11,54 , and mutation of the two Sp1-binding motifs in the gE promoter prevents VZV replication 55 . The gE promoter also has a site for upstream stimulatory factor (USF) binding, but it is not needed for the infection of tonsil T cells.…”

Section: T Cell Tropismmentioning

confidence: 99%

“…Nucleocapsids anchor at nuclear pores, where viral genomes are injected into the nucleus. VZV genome replication and viral gene expression depend on virus-encoded and host cell transcription factors and cellular translation systems 11 . Furthermore, the tegument proteins ORF47 and ORF66 are important serine/threonine kinases that autophosphorylate and phosphorylate viral transcription factors and other VZV proteins 12–18 .…”

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confidence: 99%

“…Furthermore, the tegument proteins ORF47 and ORF66 are important serine/threonine kinases that autophosphorylate and phosphorylate viral transcription factors and other VZV proteins 12–18 . IE62 forms regulatory complexes with cellular factors, such as transcription factor specificity protein 1 (Sp1), which has binding sites in many viral promoters 11 , to transactivate VZV genes. Similarly to other herpesviruses, nucleocapsids undergo primary envelopment, fusion with nuclear membranes and de-envelopment during transfer to the cytoplasm (FIG.…”

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confidence: 99%

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Molecular mechanisms of varicella zoster virus pathogenesis

et al. 2014

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Varicella zoster virus (VZV) is the causative agent of varicella (chickenpox) and zoster (shingles). Investigating VZV pathogenesis is challenging as VZV is a human-specific virus and infection does not occur, or is highly restricted, in other species. However, the use of human tissue xenografts in mice with severe combined immunodeficiency (SCID) enables the analysis of VZV infection in differentiated human cells in their typical tissue microenvironment. Xenografts of human skin, dorsal root ganglia or foetal thymus that contains T cells can be infected with mutant viruses or in the presence of inhibitors of viral or cellular functions to assess the molecular mechanisms of VZV–host interactions. In this Review, we discuss how these models have improved our understanding of VZV pathogenesis.

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Section: T Cell Tropismmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Molecular mechanisms of varicella zoster virus pathogenesis

et al. 2014

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“…The first ORF62 mutation involved nucleotide (nt) 107252 and converted a serine to a glycine. This mutation fell within region II of the IE62 amino acid sequence (28). Region II is the most highly conserved region within the IE62 regulatory protein and its homologs in other herpesviruses.…”

Section: Resultsmentioning

confidence: 98%

The Attenuated Genotype of Varicella-Zoster Virus Includes an ORF0 Transitional Stop Codon Mutation

Peters

Tyler

Carpenter

et al. 2012

J Virol

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Varicella-zoster virus (VZV) is the first of the human herpesviruses to be attenuated and subsequently approved as a live vaccine to prevent varicella and herpes zoster. Both the attenuated VZV vaccine, called vaccine Oka or vOka, and the parental strain pOka have been completely sequenced. Yet the specific determinants of attenuation are uncertain. The open reading frame (ORF) with the most single nucleotide polymorphisms (SNPs), ORF62, encodes the regulatory protein IE62, but IE62 studies have failed to define a specific SNP associated with attenuation. We have completed next-generation sequencing of the VZV Ellen genome, a strain known to be highly attenuated by its very limited replication in human skin xenografts in the SCID mouse model of VZV pathogenesis. A comparative analysis of the Ellen sequence with all other complete VZV sequences was extremely informative. In particular, an unexpected finding was a stop codon mutation in Ellen ORF0 (herpes simplex virus UL56 homolog) identical to one found in vOka, combined with the absence of polymorphisms in most Ellen ORFs that were known to be mutated in vOka. The mutated ORF0 protein was also imaged in both two dimensions and three dimensions by confocal microscopy. The probability of two VZV strains not connected by a recent common ancestor having an identical ORF0 SNP by chance would be 1 × 10 −8 , in other words, extremely unlikely. Taken together, these bioinformatics analyses strongly suggest that the stop codon ORF0 SNP is one of the determinants of the attenuation genotype of live VZV vaccines.

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“…Varicella-zoster virus (VZV), a ubiquitous neurotropic herpesvirus, has the smallest genome among the human alphaherpesviruses (12). To date, 74 open reading frames (ORFs) have been identified within the 124,884-bp VZV genome.…”

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confidence: 99%

Occupancy of RNA Polymerase II Phosphorylated on Serine 5 (RNAP S5 ^P ) and RNAP S2 ^P on Varicella-Zoster Virus Genes 9, 51, and 66 Is Independent of Transcript Abundance and Polymerase Location within the Gene

Henderson

Timberlake

Austin

et al. 2016

J Virol

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Regulation of gene transcription in varicella-zoster virus (VZV), a ubiquitous human neurotropic alphaherpesvirus, requires coordinated binding of multiple host and virus proteins onto specific regions of the virus genome. Chromatin immunoprecipitation (ChIP) is widely used to determine the location of specific proteins along a genomic region. Since the size range of sheared virus DNA fragments governs the limit of accurate protein localization, particularly for compact herpesvirus genomes, we used a quantitative PCR (qPCR)-based assay to determine the efficiency of VZV DNA shearing before ChIP, after which the assay was used to determine the relationship between transcript abundance and the occupancy of phosphorylated RNA polymerase II (RNAP) on the gene promoter, body, and terminus of VZV genes 9, 51, and 66. The abundance of VZV gene 9, 51, and 66 transcripts in VZV-infected human fetal lung fibroblasts was determined by reverse transcription-linked quantitative PCR. Our results showed that the C-terminal domain of RNAP is hyperphosphorylated at serine 5 (S5 P ) on VZV genes 9, 51, and 66 independently of transcript abundance and the location within the virus gene at both 1 and 3 days postinfection (dpi). In contrast, phosphorylated serine 2 (S2 P )-modified RNAP was not detected at any virus gene location at 3 dpi and was detected at levels only slightly above background levels at 1 dpi. IMPORTANCERegulation of herpesvirus gene transcription is an elaborate choreography between proteins and DNA that is revealed by chromatin immunoprecipitation (ChIP). We used a quantitative PCR-based assay to determine fragment size after DNA shearing, a critical parameter in ChIP assays, and exposed a basic difference in the mechanism of transcription between mammalian cells and VZV. We found that hyperphosphorylation at serine 5 of the C-terminal domain of RNAP along the lengths of VZV genes (the promoter, body, and transcription termination site) was independent of mRNA abundance. In contrast, little to no enrichment of serine 3 phosphorylation of RNAP was detected at these virus gene regions. This is distinct from the findings for RNAP at highly regulated host genes, where RNAP S5 P occupancy decreased and S2 P levels increased as the polymerase transited through the gene. Overall, these results suggest that RNAP associates with human and virus transcriptional units through different mechanisms. C hromatin immunoprecipitation (ChIP) has been used to determine the association of proteins with DNA in cells of humans (1), mice (2), Drosophila melanogaster (3), Caenorhabditis elegans (4), and Saccharomyces cerevisiae yeast (5) and has shown that gene regulation requires the interaction of multiple nuclear proteins, including RNA polymerase II (RNAP), with various transcription factors across the genome. ChIP has also been used to explore the phosphorylation status of the C-terminal domain (CTD) of RNAP at different positions along a transcription unit and showed that in eukaryotes, phosphorylation of serine 5 (S5 P )...

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Roles of Cellular Transcription Factors in VZV Replication

Cited by 12 publications

References 112 publications

Molecular mechanisms of varicella zoster virus pathogenesis

Molecular mechanisms of varicella zoster virus pathogenesis

The Attenuated Genotype of Varicella-Zoster Virus Includes an ORF0 Transitional Stop Codon Mutation

Occupancy of RNA Polymerase II Phosphorylated on Serine 5 (RNAP S5 ^P ) and RNAP S2 ^P on Varicella-Zoster Virus Genes 9, 51, and 66 Is Independent of Transcript Abundance and Polymerase Location within the Gene

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Roles of Cellular Transcription Factors in VZV Replication

Cited by 12 publications

References 112 publications

Molecular mechanisms of varicella zoster virus pathogenesis

Molecular mechanisms of varicella zoster virus pathogenesis

The Attenuated Genotype of Varicella-Zoster Virus Includes an ORF0 Transitional Stop Codon Mutation

Occupancy of RNA Polymerase II Phosphorylated on Serine 5 (RNAP S5 P ) and RNAP S2 P on Varicella-Zoster Virus Genes 9, 51, and 66 Is Independent of Transcript Abundance and Polymerase Location within the Gene

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Occupancy of RNA Polymerase II Phosphorylated on Serine 5 (RNAP S5 ^P ) and RNAP S2 ^P on Varicella-Zoster Virus Genes 9, 51, and 66 Is Independent of Transcript Abundance and Polymerase Location within the Gene