HSV-1 exploits host heterochromatin for egress [RNA-seq]
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ABSTRACT:
PROVIDER: PRJNA861940 | ENA |
REPOSITORIES: ENA
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Project description:HSV-1 exploits host heterochromatin for nuclear egress
| PRJNA862527 | ENA
Project description:HSV-1 exploits host heterochromatin for egress [CUT&Tag]
| PRJNA858438 | ENA
Project description:Herpes simplex virus replicates and forms progeny in the nucleus where it must overcome host chromatin to establish a successful infection. During lytic infection, newly formed viral capsids navigate through heterochromatin channels at the nuclear periphery to egress out of the nucleus. In uninfected cells, specific histone marks such as trimethylation on histone H3 lysine 27 (H3K27me3) and the histone variant macroH2A1 delineate heterochromatin regions, or repressed chromatin, that are predominantly located in the nuclear periphery. We examined these markers during HSV-1 lytic infection in primary cells and discovered a striking increase in the levels of macroH2A1 and H3K27me3. Here, we demonstrate that the loss of macroH2A1 results in significantly lower viral titers but does not impair viral transcription, protein production, or replication. By inhibiting the deposition of H3K27me3 by EZH2, we further show that reduction of H3K27me3 also leads to a significant decrease in viral titers. Through chromatin profiling via Cleavage Under Targets and tagmentation (CUT&Tag) of macroH2A1 and H3K27me3, we define the specific chromatin regions that change dynamically during HSV-1 lytic infection and show that regions with increased macroH2A1 and H3K27me3 correlate with decreased host transcription as measured by RNA-seq. Furthermore, we find by electron microscopy that loss of macroH2A1 results in reduced heterochromatin at the nuclear periphery and significantly more viral capsids trapped in the nuclear compartment. Using both high and low shedding clinical isolates of HSV-1, we similarly find that HSV-1 titers are significantly reduced in the absence of macroH2A1. Our work demonstrates that HSV-1 takes advantage of the dynamic nature of host heterochromatin formation during infection for efficient viral egress from the nuclear compartment.
2023-07-01 | GSE209632 | GEO
Project description:Herpes simplex virus replicates and forms progeny in the nucleus where it must overcome host chromatin to establish a successful infection. During lytic infection, newly formed viral capsids navigate through heterochromatin channels at the nuclear periphery to egress out of the nucleus. In uninfected cells, specific histone marks such as trimethylation on histone H3 lysine 27 (H3K27me3) and the histone variant macroH2A1 delineate heterochromatin regions, or repressed chromatin, that are predominantly located in the nuclear periphery. We examined these markers during HSV-1 lytic infection in primary cells and discovered a striking increase in the levels of macroH2A1 and H3K27me3. Here, we demonstrate that the loss of macroH2A1 results in significantly lower viral titers but does not impair viral transcription, protein production, or replication. By inhibiting the deposition of H3K27me3 by EZH2, we further show that reduction of H3K27me3 also leads to a significant decrease in viral titers. Through chromatin profiling via Cleavage Under Targets and tagmentation (CUT&Tag) of macroH2A1 and H3K27me3, we define the specific chromatin regions that change dynamically during HSV-1 lytic infection and show that regions with increased macroH2A1 and H3K27me3 correlate with decreased host transcription as measured by RNA-seq. Furthermore, we find by electron microscopy that loss of macroH2A1 results in reduced heterochromatin at the nuclear periphery and significantly more viral capsids trapped in the nuclear compartment. Using both high and low shedding clinical isolates of HSV-1, we similarly find that HSV-1 titers are significantly reduced in the absence of macroH2A1. Our work demonstrates that HSV-1 takes advantage of the dynamic nature of host heterochromatin formation during infection for efficient viral egress from the nuclear compartment.
2023-07-01 | GSE208127 | GEO
Project description:Herpes simplex virus (HSV-1) progeny form in the nucleus and exit to successfully infect other cells. Newly formed capsids navigate complex chromatin architecture to reach the inner nuclear membrane (INM) and egress. Here, we demonstrate by transmission electron microscopy (TEM) that HSV-1 capsids traverse heterochromatin associated with trimethylation on histone H3 lysine 27 (H3K27me3) and the histone variant macroH2A1. Through chromatin profiling during infection, we revealed global redistribution of these marks whereby massive host genomic regions bound by macroH2A1 and H3K27me3 correlate with decreased host transcription in active compartments. We found that the loss of these markers resulted in significantly lower viral titers but did not impact viral genome or protein accumulation. Strikingly, we discovered that loss of macroH2A1 or H3K27me3 resulted in nuclear trapping of capsids. Finally, by live-capsid tracking, we quantified this decreased capsid movement. Thus, our work demonstrates that HSV-1 takes advantage of the dynamic nature of host heterochromatin formation during infection for efficient nuclear egress.
| S-EPMC10373338 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-07-01 | GSE209820 | GEO
Project description:Asexual proliferation of the Plasmodium parasites that cause malaria follow a developmental program that alternates non-canonical intraerythrocytic replication with dissemination to new host cells. We carried out a functional analysis of the Plasmodium falciparum homolog of Protein Phosphatase 1 (PfPP1), a universally conserved cell cycle factor in eukaryotes, to investigate regulation of parasite proliferation. PfPP1 is indeed required for efficient replication, but is absolutely essential for egress of parasites from host red blood cells. By phosphoproteomic and chemical-genetic analysis, we isolate two functional targets of PfPP1 for egress: a HECT E3 protein-ubiquitin ligase; and GCalpha, a fusion protein composed of a guanylyl cyclase and a phospholipid transporter domain. We hypothesize that PfPP1 regulates lipid sensing by GCalpha and demonstrate that phosphatidylcholine stimulates PfPP1-dependent egress. PfPP1 acts as a key regulator that integrates multiple cell-intrinsic pathways with external signals to direct parasite egress from host cells.
2020-08-11 | PXD018718 | Pride
Project description:Analysis of host response at the gene expression level during the genital HSV-2 reactivation. We would like to get a comprehensive overview on host gene expression and correlate them with the infiltrated immune cell types during HSV-2 reactivation. The hypothesis is that HSV-2 may evade some aspects of host immune response during the recurrent infection.
2009-10-15 | GSE18527 | GEO
Project description:Host innate immune defences play a critical role in restricting the intracellular propagation and pathogenesis of invading viral pathogens. Here we show that the histone H3.3 chaperone HIRA (histone cell cycle regulator) associates with promyelocytic leukaemia nuclear bodies (PML-NBs) to stimulate the induction of innate immune defences against herpes simplex virus 1 (HSV-1) infection. Following the activation of innate immune signalling, HIRA localized at PML-NBs in a Janus-Associated Kinase (JAK), Cyclin Dependent Kinase (CDK), and Sp100-dependent manner. RNA-seq analysis revealed that HIRA promoted the transcriptional upregulation of a broad repertoire of host genes that regulate innate immunity to HSV-1 infection, including those involved in MHC-I antigen presentation, cytokine signalling, and interferon stimulated gene (ISG) expression. ChIP-seq analysis revealed that PML, the principle scaffolding protein of PML-NBs, was required for the enrichment of HIRA onto ISGs, identifying a role for PML in the HIRA-dependent regulation of innate immunity to virus infection. Our data identifies independent roles for HIRA in the intrinsic silencing of viral gene expression and the induction of innate immune defences to restrict the initiation and propagation of HSV-1 infection, respectively. These intracellular host defences are antagonized by the HSV-1 ubiquitin ligase ICP0, which disrupts the stable recruitment of HIRA to infecting viral genomes and PML-NBs at spatiotemporally distinct phases of infection. Our study highlights the importance of histone chaperones to regulate multiple phases of intracellular immunity to virus infection, findings that are likely to be highly pertinent in the cellular restriction of many clinically important viral pathogens.
2019-03-12 | GSE128173 | GEO
Project description:Toxoplasma gondii encodes three Protein Kinase A catalytic (PKAc1-3) and one regulatory (PKAr) subunits to integrate cAMP-dependent signals. Here, we show that inactive PKAc1 is maintained at the parasite pellicle by interacting with dually acylated PKAr. Either a conditional knockdown of PKAr or the overexpression of PKAc1 results in a block in parasite division. In contrast, conditional expression of a dominant negative PKAr isoform unable to bind cAMP, triggers premature egress of parasites from infected cells. This untimely egress critically depends on parasite density and host cell acidification. A comparative phosphoproteome analysis reveals that PKA genetic inhibition significantly changed the phosphorylation profile of a putative cGMP-phosphodiesterase, PDE2. Consistently, the phenotype of PKA genetic inhibition is alleviated by chemical inhibition of the cGMP-dependent protein kinase G (PKG). A phosphodiesterase inhibitor is able to circumvent egress repression by PKA or pH neutralisation, indicating that environmental acidification and PKA signalling act as balancing regulators of cGMP degradation to control PKG-mediated egress. Collectively, these results reveal a cross-talk between PKA and PKG pathways to govern egress in T. gondii.
2017-10-12 | PXD006045 | Pride