<i>Ex Vivo</i>
            Herpes Simplex Virus Reactivation Involves a Dual Leucine Zipper Kinase-Dependent Wave of Lytic Gene Expression That Is Independent of Histone Demethylase Activity and Viral Genome Synthesis

Whitford, Abigail L; Clinton, Corinne A.; Kennedy, Emily; Dochnal, Sara; Suzich, Jon B.; Cliffe, Anna R.

doi:10.1128/jvi.00475-22

Cited by 14 publications

(8 citation statements)

References 59 publications

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“…However, during the productive replication cycle, the VP16 gene is expressed with late kinetics. During Phase I, VP16, like other late genes, is expressed in the absence of viral DNA replication 33,36,37 . Further, work from the Sawtell and Thompson labs has shown that elements within the VP16 promoter can function prior to immediate-early gene expression, specifically in neurons, and are involved in the initial depression of viral gene expression during acute infection of the ganglia 55,65 .…”

Section: Discussionmentioning

confidence: 99%

“…The activation of DLK and its downstream mediator JNK are critical steps in reactivation associated with numerous triggers in vitro and ex vivo 32,34,36,37,50 . We therefore tested whether DMXAA-induced reactivation was DLK-dependent; we focused on DMXAA as this gave the most robust reactivation.…”

Section: Innate Immune Activation Promotes Lytic Gene Expression Duri...mentioning

confidence: 99%

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Co-option of mitochondrial nucleic acid sensing pathways by HSV-1 UL12.5 for reactivation from latent Infection

Cuddy,

Flores,

Krakowiak

et al. 2024

Preprint

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SummaryAlthough viruses subvert innate immune pathways for their replication, there is evidence they can also co-opt anti-viral responses for their benefit. The ubiquitous human pathogen, Herpes Simplex Virus-1 (HSV-1), encodes a protein (UL12.5) that induces the release of mitochondrial nucleic acid into the cytosol, which activates immune sensing pathways and reduces productive replication in non-neuronal cells. HSV-1 establishes latency in neurons and can reactivate to cause disease. We found that UL12.5 is required for HSV-1 reactivation in neurons and acts to directly promote viral lytic gene expression during initial exit from latency. Further, the direct activation of innate immune sensing pathways triggered HSV reactivation and compensated for a lack of UL12.5. Finally, we found that the induction of HSV-1 lytic genes during reactivation required intact RNA and DNA sensing pathways, demonstrating that HSV-1 can both respond to and active antiviral nucleic acid sensing pathways to reactivate from a latent infection.

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Section: Discussionmentioning

confidence: 99%

Section: Innate Immune Activation Promotes Lytic Gene Expression Duri...mentioning

confidence: 99%

Co-option of mitochondrial nucleic acid sensing pathways by HSV-1 UL12.5 for reactivation from latent Infection

Cuddy,

Flores,

Krakowiak

et al. 2024

Preprint

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“…[46] The reactivation of latent neuronal herpes simplex virus (HSV) infections can cause, besides blisters and sores, severe encephalitis, and it is triggered by neuronal stress. By inducing the initial wave of the increased expression of lytic genes, DLK mediates the reactivation of latent HSV infection in different model systems [37,39,47]. In addition, an association of DLK with different kinds of cancer was found, whereby DLK mRNA expression was positively correlated with lung adenocarcinoma, pancreatic duct adenocarcinoma, sarcoma, and thymoma.…”

Section: Mouse Primary Rgcsmentioning

confidence: 99%

Regulation of the Activity of the Dual Leucine Zipper Kinase by Distinct Mechanisms

Köster,

Dethlefs,

Duque Escobar

et al. 2024

Cells

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The dual leucine zipper kinase (DLK) alias mitogen-activated protein 3 kinase 12 (MAP3K12) has gained much attention in recent years. DLK belongs to the mixed lineage kinases, characterized by homology to serine/threonine and tyrosine kinase, but exerts serine/threonine kinase activity. DLK has been implicated in many diseases, including several neurodegenerative diseases, glaucoma, and diabetes mellitus. As a MAP3K, it is generally assumed that DLK becomes phosphorylated and activated by upstream signals and phosphorylates and activates itself, the downstream serine/threonine MAP2K, and, ultimately, MAPK. In addition, other mechanisms such as protein–protein interactions, proteasomal degradation, dephosphorylation by various phosphatases, palmitoylation, and subcellular localization have been shown to be involved in the regulation of DLK activity or its fine-tuning. In the present review, the diverse mechanisms regulating DLK activity will be summarized to provide better insights into DLK action and, possibly, new targets to modulate DLK function.

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“…Samples were collected at specified hours post infection (h.p.i.). For latent infection, 6-week-old female CD-1 mice (Charles River) were anesthetized by intraperitoneal injection of ketamine hydrochloride (80 mg/kg of body weight) and xylazine hydrochloride (10 mg/kg) and inoculated with 1.5 × 10^6 PFU/eye of KOS strain HSV-1 (in a 5-μL volume) onto scarified corneas, as described previously (58). Mice were housed in accordance with institutional and National Institutes of Health guidelines on the care and use of animals in research, and all procedures were approved by the Institutional Animal Care and Use Committee of the University of Virginia.…”

Section: Cells Viruses Infection and Plasmidsmentioning

confidence: 99%

HSV-1 miRNAs are posttranscriptionaly edited in latently infected human ganglia

Zubković

Gómez-Martín

Parchure

et al. 2023

Preprint

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Viruses use miRNAs to enable efficient replication, control host defense mechanisms, and regulate latent infection. Herpes simplex virus 1 (HSV-1) expresses multiple miRNAs, whose functions are largely unknown. The evolutionary conservation of many HSV-1 miRNAs in the closely related HSV-2 suggests their functional importance. miRNAs, similar to other transcripts, can undergo various posttranscriptional modifications that may affect their biogenesis, stability and targeting. To investigate whether ADAR mediated editing occurs in HSV-1 miRNAs, we sequenced samples from latently infected human ganglia. We show that one of the six HSV-1 miRNAs (miR-H2-H8) that define HSV-1 latency, miR-H2, exhibits A-to-I hyperediting within the miRNA seed sequence. We observed the same specific miR-H2 hyperediting phenomenon in miRNAs isolated from the ganglia of latently infected mice and, to a lesser extent, during productive infection in cultured cells. Curiously, we found no evidence of editing of the encoded HSV-2 homolog in latently infected mice or in cultured cells. The efficient loading of the edited miRNAs onto the RISC complex, indicates their ability to function as miRNAs. Therefore, to investigate the potential of the edited miRNA to alter mRNA targeting, we predicted the host and viral targets. Nucleotide substitution in the seed region significantly increased the number of potential host and viral targets. Most notably, ICP4, an essential viral protein, was predicted to be an additional target. Using transfection assays, we demonstrated that edited miRNAs have the potential to regulate ICP4 in addition to the previously identified target ICP0. Our study identifies a specific hyperedited HSV-1 mRNA, miR-H2, and highlights how the virus can use a single miRNA to target multiple transcripts during persistent, latent infection.

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Ex Vivo Herpes Simplex Virus Reactivation Involves a Dual Leucine Zipper Kinase-Dependent Wave of Lytic Gene Expression That Is Independent of Histone Demethylase Activity and Viral Genome Synthesis

Abstract: Reactivation of herpes simplex virus from a latent infection is associated with clinical disease. To develop new therapeutics that prevent reactivation, it is important to understand how viral gene expression initiates following a reactivation stimulus.

Cited by 14 publications

References 59 publications

Co-option of mitochondrial nucleic acid sensing pathways by HSV-1 UL12.5 for reactivation from latent Infection

Co-option of mitochondrial nucleic acid sensing pathways by HSV-1 UL12.5 for reactivation from latent Infection

Regulation of the Activity of the Dual Leucine Zipper Kinase by Distinct Mechanisms

HSV-1 miRNAs are posttranscriptionaly edited in latently infected human ganglia

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