scholarly journals Herpes simplex virus ICP27 regulates alternative pre-mRNA polyadenylation and splicing in a sequence-dependent manner

2016 ◽  
Vol 113 (43) ◽  
pp. 12256-12261 ◽  
Author(s):  
Shuang Tang ◽  
Amita Patel ◽  
Philip R. Krause
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Splice Site ◽  
Alternative Polyadenylation ◽  
Common Mechanism ◽  
Specific Gene ◽  
Dependent Manner ◽  
Splice Sites ◽  
Cellular Genes ◽  
Simplex Virus

The herpes simplex virus (HSV) infected cell culture polypeptide 27 (ICP27) protein is essential for virus infection of cells. Recent studies suggested that ICP27 inhibits splicing in a gene-specific manner via an unknown mechanism. Here, RNA-sequencing revealed that ICP27 not only inhibits splicing of certain introns in <1% of cellular genes, but also can promote use of alternative 5′ splice sites. In addition, ICP27 induced expression of pre-mRNAs prematurely cleaved and polyadenylated from cryptic polyadenylation signals (PAS) located in intron 1 or 2 of ∼1% of cellular genes. These previously undescribed prematurely cleaved and polyadenylated pre-mRNAs, some of which contain novel ORFs, were typically intronless, <2 Kb in length, expressed early during viral infection, and efficiently exported to cytoplasm. Sequence analysis revealed that ICP27-targeted genes are GC-rich (as are HSV genes), contain cytosine-rich sequences near the 5′ splice site, and have suboptimal splice sites in the impacted intron, suggesting that a common mechanism is shared between ICP27-mediated alternative polyadenylation and splicing. Optimization of splice site sequences or mutation of nearby cytosines eliminated ICP27-mediated splicing inhibition, and introduction of C-rich sequences to an ICP27-insensitive splicing reporter conferred this phenotype, supporting the inference that specific gene sequences confer susceptibility to ICP27. Although HSV is the first virus and ICP27 is the first viral protein shown to activate cryptic PASs in introns, we suspect that other viruses and cellular genes also encode this function.

scholarly journals 17-β Estradiol Promotion of Herpes Simplex Virus Type 1 Reactivation Is Estrogen Receptor Dependent

2009 ◽  
Vol 84 (1) ◽  
pp. 565-572 ◽  
Author(s):  
Rodolfo D. Vicetti Miguel ◽  
Brian S. Sheridan ◽  
Stephen A. K. Harvey ◽  
Robert S. Schreiner ◽  
Robert L. Hendricks ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Viral Reactivation ◽  
Hormonal Contraceptives ◽  
Viral Gene ◽  
Dependent Manner ◽  
Ovariectomized Mice ◽  
Latently Infected ◽  
Simplex Virus

ABSTRACT Correlations between estrogen and herpes simplex virus (HSV) reactivation from latency have been suggested by numerous clinical reports, but causal associations are not well delineated. In a murine HSV-1 corneal infection model, we establish 17-β estradiol (17-βE) treatment of latently infected ovariectomized mice induces viral reactivation, as demonstrated by increased viral load and increased immediate-early viral gene expression in the latently infected trigeminal ganglia (TG). Interestingly, the increased HSV reactivation occurred in the absence of inhibition of viral specific CD8+ T-cell effector function. 17-βE administration increased HSV reactivation in CD45+ cell-depleted TG explant cultures, providing further support that leukocyte-independent effects on latently infected neurons were responsible for the increased reactivation. The drug-induced increases in HSV copy number were not recapitulated upon in vivo treatment of latently infected estrogen receptor alpha-deficient mice, evidence that HSV reactivation promoted by 17-βE was estrogen receptor dependent. These findings provide additional framework for the emerging conceptualization of HSV latency as a dynamic process maintained by complex interactions among multiple cooperative and competing host, viral, and environmental forces. Additional research is needed to confirm whether pregnancy or hormonal contraceptives containing 17-βE also promote HSV reactivation from latency in an estrogen receptor-dependent manner.

scholarly journals Discovery of Herpes B Virus-Encoded MicroRNAs

2009 ◽  
Vol 83 (7) ◽  
pp. 3413-3416 ◽  
Author(s):  
Michael I. Besecker ◽  
Mallory E. Harden ◽  
Guanglin Li ◽  
Xiu-Jie Wang ◽  
Anthony Griffiths
Keyword(s):  
Gene Expression ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Close Relative ◽  
Macaque Monkeys ◽  
Cellular Genes ◽  
B Virus ◽  
Herpes B Virus ◽  
Simplex Virus

ABSTRACT Herpes B virus (BV) naturally infects macaque monkeys and is a close relative of herpes simplex virus. BV can zoonotically infect humans to cause a rapidly ascending encephalitis with ∼80% mortality. Therefore, BV is a serious danger to those who come into contact with these monkeys or their tissues and cells. MicroRNAs are regulators of gene expression, and there have been reports of virus-encoded microRNAs. We hypothesize that BV-encoded microRNAs are important for the regulation of viral and cellular genes. Herein, we report the discovery of three herpes B virus-encoded microRNAs.

scholarly journals The Herpes Simplex Virus 1 UL34 Protein Interacts with a Cytoplasmic Dynein Intermediate Chain and Targets Nuclear Membrane

2000 ◽  
Vol 74 (3) ◽  
pp. 1355-1363 ◽  
Author(s):  
Guo-Jie Ye ◽  
Kevin T. Vaughan ◽  
Richard B. Vallee ◽  
Bernard Roizman
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Nuclear Membrane ◽  
Viral Proteins ◽  
Cytoplasmic Dynein ◽  
Dependent Manner ◽  
Viral Dna ◽  
Herpes Simplex Virus 1 ◽  
Simplex Virus ◽  
Intermediate Chain

ABSTRACT To express the function encoded in its genome, the herpes simplex virus 1 capsid-tegument structure released by deenvelopment during entry into cells must be transported retrograde to the nuclear pore where viral DNA is released into the nucleus. This path is essential in the case of virus entering axons of dorsal root ganglia. The objective of the study was to identify the viral proteins that may be involved in the transport. We report the following findings. (i) The neuronal isoform of the intermediate chain (IC-1a) of the dynein complex pulled down, from lysates of [35S]methionine-labeled infected cells, two viral proteins identified as the products of UL34 and UL31 open reading frames, respectively. UL34 protein is a virion protein associated with cellular membranes and phosphorylated by the viral kinase US3. UL31 protein is a largely insoluble, evenly dispersed nuclear phosphoprotein required for optimal processing and packaging of viral DNA into preformed capsids. Reciprocal pulldown experiments verified the interaction of IC-1a and UL34 protein. In similar experiments, UL34 protein was found to interact with UL31 protein and the major capsid protein ICP5. (ii) To determine whether UL34 protein is transported to the nuclear membrane, a requirement if it is involved in transport, the UL34 protein was inserted into a baculovirus vector under the cytomegalovirus major early promoter. Cells infected with the recombinant baculovirus expressed UL34 protein in a dose-dependent manner, and the UL34 protein localized primarily in the nuclear membrane. An unexpected finding was that UL34-expressing cells showed a dissociation of the inner and outer nuclear membranes reminiscent of the morphologic changes seen in cells productively infected with herpes simplex virus 1. UL34, like many other viral proteins, may have multiple functions expressed both early and late in infection.

scholarly journals The Epstein-Barr Virus SM Protein Is Functionally Similar to ICP27 from Herpes Simplex Virus in Viral Infections

2002 ◽  
Vol 76 (18) ◽  
pp. 9420-9433 ◽  
Author(s):  
Julie L. Boyer ◽  
Sankar Swaminathan ◽  
Saul J. Silverstein
Keyword(s):  
Gene Expression ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Epstein Barr Virus ◽  
Common Mechanism ◽  
Barr Virus ◽  
Epstein Barr ◽  
Simplex Virus ◽  
Sm Protein ◽  
Hsv 1

ABSTRACT The herpes simplex virus type 1 (HSV-1) ICP27 protein is an essential RNA-binding protein that shuttles between the nucleus and cytoplasm to increase the cytoplasmic accumulation of viral late mRNAs. ICP27 homologs have been identified in each of the herpesvirus subfamilies, and accumulating evidence indicates that homologs from the gammaherpesvirus subfamily function similarly to ICP27. In particular, the Epstein-Barr virus (EBV) SM protein posttranscriptionally regulates gene expression, binds RNA in vitro and in vivo, and shuttles between the nucleus and cytoplasm. To determine if these two proteins function through a common mechanism, the ability of EBV SM to complement the growth defect of an HSV-1 ICP27-null virus was examined in a transient-expression assay. ICP27 stimulated the growth of the null mutant more efficiently than did SM, but the ability of SM to compensate for the ICP27 defects suggests conservation of common functions. To assay for complementation in the context of a viral infection, the growth properties of an HSV recombinant expressing SM in an ICP27-null background were analyzed. SM stimulated growth of the recombinant, although this growth was reduced by comparison to that of an ICP27-expressing virus. By contrast, an HSV recombinant expressing an SM mutant allele defective for transactivation activity and nucleocytoplasmic shuttling did not grow at all. These results suggest that SM and ICP27 may regulate gene expression through a common pathway that is evolutionarily conserved in herpesviruses.

scholarly journals Herpes Simplex Virus Infection Stabilizes Cellular IEX-1 mRNA

2005 ◽  
Vol 79 (7) ◽  
pp. 4090-4098 ◽  
Author(s):  
Wei-Li Hsu ◽  
Holly A. Saffran ◽  
James R. Smiley
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Relative Abundance ◽  
Dependent Manner ◽  
Experimental Conditions ◽  
Viral Mrnas ◽  
Necrosis Factor Alpha ◽  
Translational Initiation ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT Herpes simplex virus (HSV) virion host shutoff protein (vhs) destabilizes cellular and viral mRNAs. Previous work from several laboratories has indicated that vhs accelerates the turnover of most host mRNAs and provided evidence that at least some of these are degraded via endonucleolytic cleavage near regions of translational initiation followed by 5′→3′ decay. In contrast, several recent reports have argued that vhs is selective, preferentially targeting a subset of mRNAs including some that bear AU-rich instability elements (such as the stress-inducible IEX-1 mRNA). These reports concluded that vhs triggers deadenylation, 3′ cleavage, and 3′→5′ decay of IEX-1 mRNA. However, we report here that HSV infection does not increase the rate of degradation of IEX-1 mRNA; rather, actinomycin D chase assays indicate that the transcript is stabilized relative to that in uninfected cells in both the presence and absence of functional vhs. Moreover, deadenylated but otherwise intact IEX-1 mRNA was readily detected in uninfected cells cultured under our experimental conditions, and its relative abundance did not increase following HSV type 1 (HSV-1) infection. We confirm that HSV infection increases the relative abundance of a discrete 0.75-kb 3′-truncated IEX-1 RNA species in a vhs-dependent manner. This truncated transcript was also detected (albeit at lower levels) in cells infected with vhs mutants and in uninfected cells, where it increased in abundance in response to tumor necrosis factor alpha, cycloheximide, and puromycin. We conclude that IEX-1 mRNA is not preferentially degraded during HSV-1 infection and that HSV-1 instead inhibits the normal turnover of this mRNA.

scholarly journals Mechanism and consequences of herpes simplex virus 1-mediated regulation of host mRNA alternative polyadenylation

2020 ◽  
Author(s):  
Xiuye Wang ◽  
Liang Liu ◽  
Adam W. Whisnant ◽  
Thomas Hennig ◽  
Lara Djakovic ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Rna Polymerase Ii ◽  
Alternative Polyadenylation ◽  
Herpes Simplex Virus 1 ◽  
Eukaryotic Gene ◽  
Cellular Stresses ◽  
Simplex Virus ◽  
Host Genes ◽  
Hsv 1

AbstractEukaryotic gene expression is extensively regulated by cellular stress and pathogen infections. We have previously shown that herpes simplex virus 1 (HSV-1) and several cellular stresses cause widespread disruption of transcription termination (DoTT) of RNA polymerase II (RNAPII) in host genes and that the viral immediate early factor ICP27 plays an important role in HSV-1-induced DoTT. Here, we show that HSV-1 infection also leads to widespread changes in alternative polyadenylation (APA) of host mRNAs. In the majority of cases, polyadenylation shifts to upstream poly(A) sites (PAS), including many intronic PAS. Mechanistically, ICP27 contributes to HSV-1-mediated APA regulation. HSV-1- and ICP27-induced activation of intronic PAS is sequence-dependent and does not involve general inhibition of U1 snRNP. HSV1-induced intronic polyadenylation is accompanied by early termination of RNAPII. Finally, HSV-1-induced mRNAs polyadenylated at intronic PAS are exported into the cytoplasm while APA isoforms with extended 3’ UTRs are sequestered in the nuclei, both preventing the expression of the full-length gene products. Together with other recent studies, our results suggest that viral infection and cellular stresses induce a multi-faceted host shutoff response that includes DoTT and changes in APA profiles.

scholarly journals Wogonin inhibits in vitro herpes simplex virus type 1 and 2 infection through modulating cellular NF-κB and MAPK pathways

2020 ◽  
Author(s):  
Ying Chu ◽  
Xiaowen Lv ◽  
Longfeng Zhang ◽  
Xingli Fu ◽  
Siwei Song ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Dependent Manner ◽  
Mapk Pathways ◽  
Simplex Virus ◽  
Hsv 1

Abstract Background: Wogonin, a naturally flavonoid-like chemical compounds, has exhibited anti-inflammatory, anti-tumor, anti-viral, neuroprotective, and anxiolytic effects through modulating a variety of signaling pathways including PI3K-Akt, p53, nuclear factor κB (NF-κB) and mitogen-activated protein kinases (MAPK). In this study, its antiviral effect against herpes simplex virus type 1 and 2 (HSV-1 and HSV-2) replication has been investigated. Results: The evidence showed that wogonin could suppress HSV-1 and -2-induced cytopathogenic effect (CPE) and reduce viral RNA transcription, protein synthesis, and titers of infectious virion particles formation in a dose-dependent manner. Time-of-drug-addition assay demonstrated that wogonin acted as a viral post-entry inhibitor . It was also found that wogonin significantly reduced HSV-induced NF-κB and MAPK pathways activation, which were proved to be significant for viral replication previously. Conclusions: Our results suggested that anti-herpes effect of wogonin may be mediated by its modulation of cellular NF-κB and JNK/p38 MAPK pathways, implying its potential application as an anti-HSV agent.

The US3 kinase of Herpes Simplex virus phosphorylates the RNA sensor RIG-I to suppress innate immunity

2021 ◽  
Author(s):  
Michiel van Gent ◽  
Jessica J. Chiang ◽  
Santoshi Muppala ◽  
Cindy Chiang ◽  
Walid Azab ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Immune Escape ◽  
Type I ◽  
Dependent Manner ◽  
Herpes Simplex Virus 1 ◽  
E3 Ligases ◽  
Immune Evasion Mechanism ◽  
Simplex Virus ◽  
Hsv 1

Recent studies demonstrated that the signaling activity of the cytosolic pathogen sensor retinoic acid-inducible gene-I (RIG-I) is modulated by a variety of post-translational modifications (PTMs) to fine-tune the antiviral type I interferon (IFN) response. Whereas K63-linked ubiquitination of the RIG-I caspase activation and recruitment domains (CARDs) catalyzed by TRIM25 or other E3 ligases activates RIG-I, phosphorylation of RIG-I at S8 and T170 represses RIG-I signal transduction by preventing the TRIM25-RIG-I interaction and subsequent RIG-I ubiquitination. While strategies to suppress RIG-I signaling by interfering with its K63-polyubiquitin-dependent activation have been identified for several viruses, evasion mechanisms that directly promote RIG-I phosphorylation to escape antiviral immunity are unknown. Here, we show that the serine/threonine (Ser/Thr) kinase US3 of herpes simplex virus 1 (HSV-1) binds to RIG-I and phosphorylates RIG-I specifically at S8. US3-mediated phosphorylation suppressed TRIM25-mediated RIG-I ubiquitination, RIG-I-MAVS binding, and type I IFN induction. We constructed a mutant HSV-1 encoding a catalytically-inactive US3 protein (K220A) and found that, in contrast to the parental virus, the US3 mutant HSV-1 is unable to phosphorylate RIG-I at S8 and elicited higher levels of type I IFNs, IFN-stimulated genes (ISGs), and proinflammatory cytokines in a RIG-I-dependent manner. Finally, we show that this RIG-I evasion mechanism is conserved among the alphaherpesvirus US3 kinase family. Collectively, our study reveals a novel immune evasion mechanism of herpesviruses in which their US3 kinases phosphorylate the sensor RIG-I to keep it in the signaling-repressed state. IMPORTANCE Herpes simplex virus 1 (HSV-1) establishes life-long latency in the majority of the human population worldwide. HSV-1 occasionally reactivates to produce infectious virus and to facilitate dissemination. While often remaining subclinical, both primary infection and reactivation occasionally cause debilitating eye diseases, which can lead to blindness, as well as life-threatening encephalitis and newborn infections. To identify new therapeutic targets for HSV-1-induced diseases, it is important to understand the HSV-1-host interactions that may influence infection outcome and disease. Our work uncovered direct phosphorylation of the pathogen sensor RIG-I by alphaherpesvirus-encoded kinases as a novel viral immune escape strategy and also underscores the importance of RNA sensors in surveilling DNA virus infection.

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