Cell responses to dysregulated VZV-induced cell-cell fusion
Ontology highlight
ABSTRACT:
OTHER RELATED OMICS DATASETS IN: GSE85493
PROVIDER: PRJNA338650 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR4019610.fastq.gz | Fastqsanger.gz | |||
| SRR4019620.fastq.gz | Fastqsanger.gz | |||
| SRR4019630.fastq.gz | Fastqsanger.gz | |||
| SRR4019611.fastq.gz | Fastqsanger.gz | |||
| SRR4019621.fastq.gz | Fastqsanger.gz |
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Project description:The highly conserved herpesvirus glycoprotein complex, gB/gH-gL, mediates membrane fusion during virion entry and cell-cell fusion. Varicella-zoster virus (VZV) characteristically forms multi-nucleated cells, or syncytia, during the infection of human tissues but little is known about this process. The cytoplasmic domain of VZV gB (gBcyt) has been implicated in cell-cell fusion regulation because a gB[Y881F] substitution causes hyperfusion. The gBcyt regulation is necessary for VZV pathogenesis as the hyperfusogenic mutant gB[Y881F] is severely attenuated in human skin xenografts. In this study, gBcyt regulated fusion was investigated by comparing melanoma cells infected with wild type-like VZV or hyperfusogenic mutants. The gB[Y881F] mutant exhibited dramatically accelerated syncytia formation in melanoma cells caused by fusion of infected cells with many uninfected cells, increased cytoskeleton reorganization and rapid displacement of nuclei to dense central structures when compared to pOka using live cell confocal microscopy. VZV and human transcriptomes were concurrently investigated using RNA-seq to identify viral and cellular responses induced when the gBcyt regulation was disrupted by the gB[Y881F] substitution. The expression of four vital VZV genes, ORF61 and glycoproteins, gC, gE and gI, was significantly reduced at 36 hours post infection for the hyperfusogenic mutants. Importantly, hierarchical clustering demonstrated an association of differential gene expression with dysregulated gBcyt-mediated fusion. A subset of Ras GTPase genes linked to membrane remodeling were upregulated in cells infected with the hyperfusogenic mutants. These data implicate the gBcyt in the regulation gB fusion function that, if unmodulated, triggers cellular processes leading to hyperfusion that attenuates VZV infection.
2017-03-01 | GSE85493 | GEO
Project description:Our aim was to investigate the interaction between epidermal differentiation and VZV infection. By means of a calcium-induced keratinocyte differentiation model and RNA-seq we show VZV infection has a profound effect on differentiating keratinocytes and hijacks the normal process of epidermal gene expression to generate a signature resembling patterns of gene expression seen in both heritable and acquired skin-blistering disorders. Analysis of the viral transcriptome provides evidence that VZV replication in skin is tightly linked to differentiation and critically, that late viral gene expression is associated with cellular differentiation. The experiment was performed on human primary keratinocytes under four conditions: undifferentiated/uninfected, uninfected/differentiated, VZV-infected/undifferentiated and VZV-infected/differentiated.
2014-05-29 | E-MTAB-1717 | biostudies-arrayexpress
Project description:Anaplastic lymphoma kinase (ALK) fusion variants in non-small-cell-lung cancer (NSCLC) consist of numerous dimerising fusion partners, with the most common being EML4. Clinical data suggests that the degree of treatment benefit in response to ALK tyrosine kinase inhibitors (TKIs) differs among the variant present in the patient tumor. Therefore, a better understanding the oncogenic signaling networks driven by different ALK-fusion variants is important. Here, we developed highly controlled doxycycline-inducible cell models bearing four different ALK fusion proteins, namely EML4-ALK-V1, EML4-ALK-V3, KIF5B-ALK, and TFG-ALK, in the context of non-tumorigenic NL20 human bronchial epithelial cells. These were complimented by patient-derived NSCLC cell lines harboring either EML4-ALK-V1 or EML4-ALK-V3 fusions. RNAseq and phosphoproteomics analysis were employed to identify dysregulated genes and hyper/hypo-phosphorylated proteins associated with ALK fusion expression. Among ALK fusion induced responses, we noted a robust inflammatory signature that included up-regulation of the Serpin B4 serine protease inhibitor in both NL20-inducible cell models and ALK-positive NSCLC patient-derived cell lines. We show that STAT3 is a major transcriptional regulator of SERPINB4 downstream of ALK fusions, along with NF-B and AP1. The upregulation of SERPINB4 promotes survival of ALK fusion expressing cells and inhibits natural killer (NK) cell-mediated cytotoxicity. In conclusion, our study reveals a novel ALK downstream survival axis that regulates Serpin B4 expression and identifies a molecular target that has potential for therapeutic impact targeting the immune response together with ALK TKIs in NSCLC.
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Project description:Exosomes have emerged as essential extracellular signaling vesicles that can deliver proteins and nucleic acids to cells during normal and disease states. Herein, we studied the effects of exosomes produced by VZV-infected human sensory neurons on cerebrovascular cells. Exosomes were isolated from mock- and VZV-infected sensory neurons and protein and nucleic acid was determined by mass spectrometry and Next-Generation Sequencing. Subsequently, mock- and VZV-derived exosomes were applied to primary human brain vascular adventitial fibroblasts (HBVAFs). Overall, exosomes from VZV-infected sensory neurons impacted the pro-inflammatory phenotype of HBVAF cells. The presence of pathogenic exosomes that could circulate throughout the body provides insight into clinical infections.
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Project description:Varicella Zoster Virus (VZV) is a skin-tropic virus that infects epidermal keratinocytes and causes chickenpox. Although common, VZV infection can be life-threatening particularly in the immunocompromised. Therefore, understanding VZV-keratinocyte interactions is important to find new treatments beyond vaccination and anti-viral drugs. In VZV- infected skin, Kallikrein 6 (KLK6), and the ubiquitin-ligase MDM2 are up-regulated concomitant with Keratin 10 (K10) down-regulation. MDM2 binds to K10 targeting it for degradation via the ubiquitin-proteasome pathway. Preventing K10 degradation reduced VZV propagation in culture and prevented epidermal disruption in skin explants. K10 knockdown induced expression of the nuclear receptor subfamily 4, group A, member 1 (NR4A1) and enhanced viral propagation in culture. NR4A1 knockdown prevented viral propagation in culture, reduced LC3 levels and increased LAMP2 expression. We therefore describe a novel drug-able pathway whereby MDM2 ubiquitinates and degrades K10 increasing NR4A1 expression allowing VZV replication and propagation.
2019-08-29 | GSE136586 | GEO
Project description:Sequence analyses shown that most exons of VZV circVLTs were overlapped with ORFs, except for exon5, which was an ideal mutation position. Using a galK positive/counter selection VZV bacteria artificial chromosome (BAC) system, we replaced upstream (104,765-104,785 Mutation2, pOKA-M2) or downstream (104,785-104,805, Mutation1, pOKA-M1) of circVLTs BSJ exon5 with 20 bp random sequences in VZV genomic DNA level. The code used in this study and extended data are available from the GitHub repository (https://github.com/ShaominYang/VZV_circRNA)
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Project description:Exosomes have emerged as essential extracellular signaling vesicles that can deliver proteins and nucleic acids to cells during normal and disease states. Herein, we studied the effects of exosomes produced by VZV-infected human sensory neurons on cerebrovascular cells. Exosomes were isolated from mock- and VZV-infected sensory neurons and protein and nucleic acid was determined by mass spectrometry and Next-Generation Sequencing. Subsequently, mock- and VZV-derived exosomes were applied to primary human brain vascular adventitial fibroblasts (HBVAFs). Overall, exosomes from VZV-infected sensory neurons impacted the pro-inflammatory phenotype of HBVAF cells. The presence of pathogenic exosomes that could circulate throughout the body provides insight into clinical infections.
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Project description:Our newly developed high-throughput screening assay of bioactive compounds discovered a cellular phosphatase, calcineurin, was critical in the regulation of Varicella-Zoster Virus (VZV) glycoprotein complex gB/gH-gL mediated cell fusion. To better understand how calcineurin regulates fusion, the potential substrates for calcineurin phosphatase were investigated in human melanoma MeWo cells upon treatment with specific calcineurin phosphatase inhibitor, pimecrolimus. Phosphopeptide enrichment and Orbitrap mass spectrometry analysis identified seven proteins that were exclusively phosphorylated in MeWo cells treated with pimecrolimus compared to DMSO vehicle control, including two known calcineurin substrates. The other five proteins were novel targets for calcineurin dephosphorylation. These data implicated that one or more of these seven proteins in the calcineurin mediated regulation of VZV gB/gH-gL mediated cell fusion.
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Project description:VZV infection of primary keratinocytes
| PRJEB4204 | ENA