Herpes Simplex Virus ICP27 Increases Translation of a Subset of Viral Late mRNAs

Fontaine-Rodriguez, Errin C.; Knipe, David M.

doi:10.1128/jvi.02395-07

Cited by 72 publications

(87 citation statements)

References 50 publications

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“…Given that each mRNA was synthesized in vitro and transfected directly into cells in this assay, it is not likely that any events related to nuclear export processes were involved. The increased levels of translation could result from the direct activation of translation by ORF57 (5,13,22) or from the increased stabilization of the RNA by ORF57 (see below). Increasing levels of ORF57 protein expression were achieved from increasing inputs of ORF57 plasmid DNA.…”

Section: Resultsmentioning

confidence: 99%

Rhesus Monkey Rhadinovirus ORF57 Induces gH and gL Glycoprotein Expression through Posttranscriptional Accumulation of Target mRNAs

Shin

Desrosiers

2011

J Virol

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Open reading frame 57 (ORF57) of gamma-2 herpesviruses is a key regulator of viral gene expression. It has been reported to enhance the expression of viral genes by transcriptional, posttranscriptional, or translational activation mechanisms. Previously we have shown that the expression of gH and gL of rhesus monkey rhadinovirus (RRV), a close relative of the human Kaposi's sarcoma-associated herpesvirus (KSHV), could be dramatically rescued by codon optimization as well as by ORF57 coexpression (J. P. Bilello, J. S. Morgan, and R. C. Desrosiers, J. Virol. 82:7231-7237, 2008). We show here that ORF57 coexpression and codon optimization had similar effects, except that the rescue of expression by codon optimization was temporally delayed relative to that of ORF57 coexpression. The transfection of gL mRNA directly into cells with or without ORF57 coexpression and with or without codon optimization recapitulated the effects of these modes of induction on transfected DNA. These findings suggested an important role for the enhancement of mRNA stability and/or the translation of mRNA for these very different modes of induced expression. This conclusion was confirmed by several different measures of gH and gL mRNA stability and accumulation with or without ORF57 coexpression and with or without codon optimization. Our results indicate that RRV gH and gL expression is severely limited by the stability of the mRNA and that ORF57 coexpression and codon optimization independently induce gH and gL expression principally by allowing accumulation and translation of these mRNAs.

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Section: Resultsmentioning

confidence: 99%

Rhesus Monkey Rhadinovirus ORF57 Induces gH and gL Glycoprotein Expression through Posttranscriptional Accumulation of Target mRNAs

Shin

Desrosiers

2011

J Virol

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“…A more likely scenario is that an α protein, possibly ICP27, plays a role in enhancing the stability of viral mRNAs made later in infection. ICP27 has been reported to enhance the translation of γ mRNAs (38), but the effect may be due to stabilization of the mRNAs rather than to a specific effect on the translational machinery of the infected cell. It is noteworthy, as shown in this report, that ICP27 mediates a posttranslational modification as well as enhancement of accumulation of U L 47 in cotransfected cells (Fig.…”

Section: Discussionmentioning

confidence: 99%

Selective degradation of mRNAs by the HSV host shutoff RNase is regulated by the U _L 47 tegument protein

Shu

Taddeo

Zhang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Herpes simplex virus 1 (HSV-1) encodes an endoribonuclease that is responsible for the shutoff of host protein synthesis [virion host shutoff (VHS)-RNase]. The VHS-RNase released into cells during infection targets differentially four classes of mRNAs. Thus, (a) VHSRNase degrades stable cellular mRNAs and α (immediate early) viral mRNAs; (b) it stabilizes host stress response mRNAs after deadenylation and subsequent cleavage near the adenylate-uridylate (AU)-rich elements; (c) it does not effectively degrade viral β or γ mRNAs; and (d) it selectively spares from degradation a small number of cellular mRNAs. Current evidence suggests that several viral and at least one host protein (tristetraprolin) regulate its activity. Thus, virion protein (VP) 16 and VP22 neutralize the RNase activity at late times after infection. By binding to AU-rich elements via its interaction with tristetraprolin, the RNase deadenylates and cleaves the mRNAs in proximity to the AU-rich elements. In this report we show that another virion protein, U L 47, brought into the cell during infection, attenuates the VHS-RNase activity with respect to stable host and viral α mRNAs and effectively blocks the degradation of β and γ mRNAs, but it has no effect on the processing of AU-rich mRNAs. The properties of U L 47 suggest that it, along with the α protein infected cell protein 27, attenuates degradation of mRNAs by the VHS-RNase through interaction with the enzyme in polyribosomes. Mutants lacking both VHS-RNase and U L 47 overexpress α genes and delay the expression of β and γ genes, suggesting that overexpression of α genes inhibits the downstream expression of early and late genes.innate immunity | host response A ttachment and entry of herpes simplex virus 1 (HSV-1) provokes powerful innate immune responses to the virus. HSV-1 blocks the responses in two fundamentally different ways, by bringing into cells at the time of entry both tegument proteins and prepackaged mRNAs and by encoding proteins made immediately after infection with numerous functions designed to block host innate immune responses (1-5). Among the best-known and highly effective tegument proteins actively blocking host responses is the virion host shutoff RNase encoded by the U L 41 ORF (6-8). This RNase is an endoribonuclease with the specificity of RNase A (9), and it is active immediately after entry of the virus into cells and during the initial stages of infection. The primary function of VHSRNase appears to be the degradation of mRNAs made in response to infection, but it also prevents, by a mechanism not fully understood, the activation of protein kinase R (10-12). At late stages in the viral replicative cycle, virion host shutoff (VHS)-RNase activity is blocked or neutralized by two late proteins, virion protein (VP) 16 and VP22, encoded by U L 48 and U L 49 ORFs, respectively (13,14). The RNase cleaves mRNA in polyribosomes (15). Another partner of the VHS-RNase present in polyribosomes is infected cell protein (ICP) 27, an α (immediate early) multifunctional reg...

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“…Because studies of viruses have proved highly informative for the understanding of cellular translational regulation, we examined the mechanism of action of ICP27, an essential herpes simplex virus type 1 (HSV-1) protein that is a key regulator of host and viral gene expression (6). ICP27 regulates the translation of a subset of viral mRNAs, including the viral mRNAs encoding VP16 and ICP5 (7,8), via an uncharacterized mechanism. This effect is mRNA-specific, because the translation of other studied viral and cellular mRNAs is not ICP27-dependent (7,8).…”

Section: Significancementioning

confidence: 99%

Viral and cellular mRNA-specific activators harness PABP and eIF4G to promote translation initiation downstream of cap binding

Smith

Anderson

Larralde

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Regulation of mRNA translation is a major control point for gene expression and is critical for life. Of central importance is the complex between cap-bound eukaryotic initiation factor 4E (eIF4E), eIF4G, and poly(A) tail-binding protein (PABP) that circularizes mRNAs, promoting translation and stability. This complex is often targeted to regulate overall translation rates, and also by mRNA-specific translational repressors. However, the mechanisms of mRNA-specific translational activation by RNA-binding proteins remain poorly understood. Here, we address this deficit, focusing on a herpes simplex virus-1 protein, ICP27. We reveal a direct interaction with PABP that is sufficient to promote PABP recruitment and necessary for ICP27-mediated activation. PABP binds several translation factors but is primarily considered to activate translation initiation as part of the PABP-eIF4G-eIF4E complex that stimulates the initial cap-binding step. Importantly, we find that ICP27-PABP forms a complex with, and requires the activity of, eIF4G. Surprisingly, ICP27-PABP-eIF4G complexes act independently of the effects of PABP-eIF4G on cap binding to promote small ribosomal subunit recruitment. Moreover, we find that a cellular mRNA-specific regulator, Deleted in Azoospermia-like (Dazl), also employs the PABP-eIF4G interaction in a similar manner. We propose a mechanism whereby diverse RNA-binding proteins directly recruit PABP, in a non-poly(A) tail-dependent manner, to stimulate the small subunit recruitment step. This strategy may be particularly relevant to biological conditions associated with hypoadenylated mRNAs (e.g., germ cells/neurons) and/or limiting cytoplasmic PABP (e.g., viral infection, cell stress). This mechanism adds significant insight into our knowledge of mRNA-specific translational activation and the function of the PABP-eIF4G complex in translation initiation.D espite the importance of translational control, the mechanisms by which specific subsets of mRNAs are translationally regulated are only well defined in a handful of cases. Nevertheless, it is clear that regulation is most often mediated by factors recruited to the 3′ untranslated region (UTR) of mRNAs and frequently occurs at the level of initiation (1). Initiation is a multistep process involving several mRNA-dependent steps, each of which requires eukaryotic initiation factors (eIFs) (2). Initially, the m 7 GpppX cap is bound by eIF4F, comprising a large scaffold protein, eIF4G, bound to the cap-binding protein, eIF4E, and an RNA helicase, eIF4A. The small (40S) ribosomal subunit, initiator tRNA, and associated initiation factors are then recruited as a 43S preinitiation complex. Recruitment is facilitated by eIF4A-dependent removal of RNA secondary structure and by the interaction of 40S-associated eIF3 with eIF4G. The 43S small ribosomal subunit complex then scans the 5′ UTR to locate a start codon, recognition of which promotes release of initiation factors and joining of the large (60S) ribosomal subunit to form an 80S ribosome. Like the cap,...

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Herpes Simplex Virus ICP27 Increases Translation of a Subset of Viral Late mRNAs

Cited by 72 publications

References 50 publications

Rhesus Monkey Rhadinovirus ORF57 Induces gH and gL Glycoprotein Expression through Posttranscriptional Accumulation of Target mRNAs

Rhesus Monkey Rhadinovirus ORF57 Induces gH and gL Glycoprotein Expression through Posttranscriptional Accumulation of Target mRNAs

Selective degradation of mRNAs by the HSV host shutoff RNase is regulated by the U _L 47 tegument protein

Viral and cellular mRNA-specific activators harness PABP and eIF4G to promote translation initiation downstream of cap binding

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Herpes Simplex Virus ICP27 Increases Translation of a Subset of Viral Late mRNAs

Cited by 72 publications

References 50 publications

Rhesus Monkey Rhadinovirus ORF57 Induces gH and gL Glycoprotein Expression through Posttranscriptional Accumulation of Target mRNAs

Rhesus Monkey Rhadinovirus ORF57 Induces gH and gL Glycoprotein Expression through Posttranscriptional Accumulation of Target mRNAs

Selective degradation of mRNAs by the HSV host shutoff RNase is regulated by the U L 47 tegument protein

Viral and cellular mRNA-specific activators harness PABP and eIF4G to promote translation initiation downstream of cap binding

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About

Selective degradation of mRNAs by the HSV host shutoff RNase is regulated by the U _L 47 tegument protein