Human herpesvirus miRNAs statistically preferentially target host genes involved in cell signaling and adhesion/junction pathways

Gao, Ge; Li, Jiong-Tang; Kong, Lei; Tao, Louis; Wei, Liping

doi:10.1038/cr.2009.45

Cited by 10 publications

(7 citation statements)

References 14 publications

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“…These LAT small non-coding RNA interfere with apoptosis and ICP4 expression [47] suggesting they also play a role in the latency-reactivation cycle. Analysis of the known miRNAs encoded by the human herpesviruses are reported to preferentially target the Wnt signaling pathway [48], which supports the premise that stabilizing β-catenin expression in TG neurons during latency is important for maintaining a life-long latent infection in sensory neurons.…”

Section: Plos Onementioning

confidence: 57%

Herpes simplex virus 1 regulates β-catenin expression in TG neurons during the latency-reactivation cycle

et al. 2020

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When herpes simplex virus 1 (HSV-1) infection is initiated in the ocular, nasal, or oral cavity, sensory neurons within trigeminal ganglia (TG) become infected. Following a burst of viral transcription in TG neurons, lytic cycle viral genes are suppressed and latency is established. The latency-associated transcript (LAT) is the only viral gene abundantly expressed during latency, and LAT expression is important for the latency-reactivation cycle. Reactivation from latency is required for virus transmission and recurrent disease, including encephalitis. The Wnt/β-catenin signaling pathway is differentially expressed in TG during the bovine herpesvirus 1 latency-reactivation cycle. Hence, we hypothesized HSV-1 regulates the Wnt/β-catenin pathway and promotes maintenance of latency because this pathway enhances neuronal survival and axonal repair. New studies revealed β-catenin was expressed in significantly more TG neurons during latency compared to TG from uninfected mice or mice latently infected with a LAT -/mutant virus. When TG explants were incubated with media containing dexamethasone to stimulate reactivation, significantly fewer β-cate-nin+ TG neurons were detected. Conversely, TG explants from uninfected mice or mice latently infected with a LAT -/mutant increased the number of β-catenin+ TG neurons in the presence of DEX relative to samples not treated with DEX. Impairing Wnt signaling with small molecule antagonists reduced virus shedding during explant-induced reactivation. These studies suggested β-catenin was differentially expressed during the latency-reactivation cycle, in part due to LAT expression. OPEN ACCESS Citation: Harrison KS, Zhu L, Thunuguntla P, Jones C (2020) Herpes simplex virus 1 regulates βcatenin expression in TG neurons during the latency-reactivation cycle. PLoS ONE 15(3): e0230870. https://doi.

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Section: Plos Onementioning

confidence: 57%

Herpes simplex virus 1 regulates β-catenin expression in TG neurons during the latency-reactivation cycle

et al. 2020

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“…The ability of ORF2 to enhance ␤-catenin-dependent transcription in transfected cells (21) correlates with stabilizing the Wnt/␤-catenin signaling pathway during latency. Other viral gene products may also be involved, because two virus-encoded micro-RNAs and ORF1 are expressed in certain latently infected neurons (8), and other herpesvirus-encoded micro-RNAs were proposed to regulate the Wnt signaling pathway (84). Regardless of which LR gene products are involved, Wnt/␤-catenin agonists, including GNAQ, Wnt16,…”

Section: Discussionmentioning

confidence: 99%

The Wnt Signaling Pathway Is Differentially Expressed during the Bovine Herpesvirus 1 Latency-Reactivation Cycle: Evidence That Two Protein Kinases Associated with Neuronal Survival, Akt3 and BMPR2, Are Expressed at Higher Levels during Latency

Workman

Zhu

Keel

et al. 2018

J Virol

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Sensory neurons in trigeminal ganglia (TG) of calves latently infected with bovine herpesvirus 1 (BoHV-1) abundantly express latency-related (LR) gene products, including a protein (ORF2) and two micro-RNAs. Recent studies in mouse neuroblastoma cells (Neuro-2A) demonstrated ORF2 interacts with β-catenin and a β-catenin coactivator, high-mobility group AT-hook 1 (HMGA1) protein, which correlates with increased β-catenin-dependent transcription and cell survival. β-Catenin and HMGA1 are readily detected in a subset of latently infected TG neurons but not TG neurons from uninfected calves or reactivation from latency. Consequently, we hypothesized that the Wnt/β-catenin signaling pathway is differentially expressed during the latency and reactivation cycle and an active Wnt pathway promotes latency. RNA-sequencing studies revealed that 102 genes associated with the Wnt/β-catenin signaling pathway were differentially expressed in TG during the latency-reactivation cycle in calves. Wnt agonists were generally expressed at higher levels during latency, but these levels decreased during dexamethasone-induced reactivation. The Wnt agonist bone morphogenetic protein receptor 2 (BMPR2) was intriguing because it encodes a serine/threonine receptor kinase that promotes neuronal differentiation and inhibits cell death. Another differentially expressed gene encodes a protein kinase (Akt3), which is significant because Akt activity enhances cell survival and is linked to herpes simplex virus 1 latency and neuronal survival. Additional studies demonstrated ORF2 increased Akt3 steady-state protein levels and interacted with Akt3 in transfected Neuro-2A cells, which correlated with Akt3 activation. Conversely, expression of Wnt antagonists increased during reactivation from latency. Collectively, these studies suggest Wnt signaling cooperates with LR gene products, in particular ORF2, to promote latency. Lifelong BoHV-1 latency primarily occurs in sensory neurons. The synthetic corticosteroid dexamethasone consistently induces reactivation from latency in calves. RNA sequencing studies revealed 102 genes associated with the Wnt/β-catenin signaling pathway are differentially regulated during the latency-reactivation cycle. Two protein kinases associated with the Wnt pathway, Akt3 and BMPR2, were expressed at higher levels during latency but were repressed during reactivation. Furthermore, five genes encoding soluble Wnt antagonists and β-catenin-dependent transcription inhibitors were induced during reactivation from latency. These findings are important because Wnt, BMPR2, and Akt3 promote neurogenesis and cell survival, processes crucial for lifelong viral latency. In transfected neuroblastoma cells, a viral protein expressed during latency (ORF2) interacts with and enhances Akt3 protein kinase activity. These findings provide insight into how cellular factors associated with the Wnt signaling pathway cooperate with LR gene products to regulate the BoHV-1 latency-reactivation cycle.

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“…A previous analysis showed enrichment for KEGG pathways associated with cell signaling and adhesion/junction pathways using the putative targets of 85 known miRNAs in 5 human herpes virus as an aggregate (not virus-specific or miRNA-specific) [19]. Another study of known KSHV miRNAs and targets predicted by differential expression analysis found the targets to be involved in proliferation, immune modulation, angiogenesis, and apoptosis [31].…”

Section: Discussionmentioning

confidence: 99%

“…If the suppression of a host gene disables host defense or enables viral survival or proliferation (e.g., by promoting cell growth, or inducing repair mechanisms to aid the survival of the infected cell), then encoding a miRNA that targets the specific host gene would potentially benefit the virus. While a few previous studies support this suggestion with specific examples in a limited context [10,19,20], it is not clear whether there are shared patterns among different viral miRNAs targeting different hosts. Here we investigate the general patterns of cellular targeting by viral miRNAs for a comprehensive set of human and murine viruses.…”

Section: Introductionmentioning

confidence: 92%

Widespread evidence of viral miRNAs targeting host pathways

2013

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Background MicroRNAs (miRNA) are regulatory genes that target and repress other RNA molecules via sequence-specific binding. Several biological processes are regulated across many organisms by evolutionarily conserved miRNAs. Plants and invertebrates employ their miRNA in defense against viruses by targeting and degrading viral products. Viruses also encode miRNAs and there is evidence to suggest that virus-encoded miRNAs target specific host genes and pathways that may be beneficial for their infectivity and/or proliferation. However, it is not clear whether there are general patterns underlying cellular targets of viral miRNAs. Results Here we show that for several of the 135 known viral miRNAs in human viruses, the human genes targeted by the viral miRNA are enriched for specific host pathways whose targeting is likely beneficial to the virus. Given that viral miRNAs continue to be discovered as technologies evolve, we extended the investigation to 6809 putative miRNAs encoded by 23 human viruses. Our analysis further suggests that human viruses have evolved their miRNA repertoire to target specific human pathways, such as cell growth, axon guidance, and cell differentiation. Interestingly, many of the same pathways are also targeted in mice by miRNAs encoded by murine viruses. Furthermore, Human Cytomegalovirus (CMV) miRNAs that target specific human pathways exhibit increased conservation across CMV strains. Conclusions Overall, our results suggest that viruses may have evolved their miRNA repertoire to target specific host pathways as a means for their survival.

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Human herpesvirus miRNAs statistically preferentially target host genes involved in cell signaling and adhesion/junction pathways

Cited by 10 publications

References 14 publications

Herpes simplex virus 1 regulates β-catenin expression in TG neurons during the latency-reactivation cycle

Herpes simplex virus 1 regulates β-catenin expression in TG neurons during the latency-reactivation cycle

The Wnt Signaling Pathway Is Differentially Expressed during the Bovine Herpesvirus 1 Latency-Reactivation Cycle: Evidence That Two Protein Kinases Associated with Neuronal Survival, Akt3 and BMPR2, Are Expressed at Higher Levels during Latency

Widespread evidence of viral miRNAs targeting host pathways

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