Epstein-Barr Virus mRNA Export Factor EB2 Is Essential for Production of Infectious Virus

Gruffat, Henri; Batisse, Julien; Pich, Dagmar; Nęuhierl, Bernhard; Manet, Évelyne; Hammerschmidt, Wolfgang; Sergeant, Alain

doi:10.1128/jvi.76.19.9635-9644.2002

Cited by 78 publications

(138 citation statements)

References 51 publications

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“…Use of combination therapy with agents directed against different steps in the viral life cycle also has the potential to limit the emergence of drug resistance. Each human herpesvirus expresses an SM homolog that is essential for virus production (3,(26)(27)(28). Although they generally do not crosscomplement each other in rescuing viral replication (3,26,29), they are structurally and functionally similar.…”

Section: Discussionmentioning

confidence: 99%

“…SM acts posttranscriptionally to enhance accumulation of many lytic EBV transcripts. SM activity is highly gene-specific and preferentially enhances expression of several late lytic transcripts, including those encoding the major viral capsid antigen (VCA) and gp350, which is required for infection of B lymphocytes (3)(4)(5). SM and its homologs in other herpesviruses may also enhance transcription and translation of specific viral genes (6).…”

mentioning

confidence: 99%

“…We previously described a screening assay to identify compounds that can inhibit the function of EBV SM protein, which is essential for lytic EBV replication (3,8). The assay is based on the finding that mRNAs dependent on EBV SM protein for efficient expression confer SM dependence on heterologous genes to which they are fused.…”

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confidence: 99%

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Spironolactone blocks Epstein–Barr virus production by inhibiting EBV SM protein function

Verma

Thompson

Swaminathan

2016

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

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Clinically available drugs active against Epstein-Barr virus (EBV) and other human herpesviruses are limited to those targeting viral DNA replication. To identify compounds directed against other steps in the viral life cycle, we searched for drugs active against the EBV SM protein, which is essential for infectious virus production. SM has a highly gene-specific mode of action and preferentially enhances expression of several late lytic cycle EBV genes. Here we demonstrate that spironolactone, a mineralocorticoid receptor antagonist approved for clinical use, inhibits SM function and infectious EBV production. Expression of EBV viral capsid antigen is highly SM dependent, and spironolactone inhibits viral capsid antigen synthesis and capsid formation, blocking EBV virion production at a step subsequent to viral DNA replication. In addition, spironolactone inhibits expression of other SM-dependent genes necessary for infectious virion formation. We further demonstrate that molecules structurally related to spironolactone with similar antimineralocorticoid blocking activity do not inhibit EBV production. These findings pave the way for development of antiherpesvirus drugs with new mechanisms of action directed against SM and homologous essential proteins in other herpesviruses. . EBV infects the majority of humans worldwide and establishes a persistent, lifelong latent infection in memory B cells. Occasional reactivation from latency occurs, and EBV enters a lytic phase of replication, during which a tightly regulated series of lytic genes is expressed, culminating in lysis of the host cell and release of infectious viral progeny. All herpesviruses share these abilities to establish asymptomatic latent infection and reactivate intermittently.All herpesviruses also express a regulatory protein early in lytic replication that is essential for efficient gene expression and infectious virion production. The EBV member of this family, which includes herpes simplex virus ICP27, cytomegalovirus (CMV) UL69, and Kaposi's sarcoma-associated herpesvirus (KSHV) ORF57, is known as SM (2). SM acts posttranscriptionally to enhance accumulation of many lytic EBV transcripts. SM activity is highly gene-specific and preferentially enhances expression of several late lytic transcripts, including those encoding the major viral capsid antigen (VCA) and gp350, which is required for infection of B lymphocytes (3-5). SM and its homologs in other herpesviruses may also enhance transcription and translation of specific viral genes (6).Currently, all available antiherpesvirus drugs target viral DNA polymerases and are usually highly effective, but toxicity and development of resistance limits their use (7). To discover potential novel therapeutic compounds, we applied a cell-based screening assay to identify compounds that would specifically target SM function (8). Using this assay, spironolactone (SPR), a drug in clinical use for over 50 y, was identified as inhibiting SM function and EBV virion production. SPR is an aldosterone antagonis...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Spironolactone blocks Epstein–Barr virus production by inhibiting EBV SM protein function

Verma

Thompson

Swaminathan

2016

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

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“…Such genes are conserved among all human herpesviruses, suggesting a conserved function for their products. At least for HSV-1 and EBV, the inactivation of ICP27 (11) or EB2 (12), respectively, abolishes the production of infectious viral particles, demonstrating that ICP27 and EB2 are essential factors for viral mRNA export and that their function cannot be trans-complemented by cellular factors. Moreover, EB2 appears to have an effect on cellular mRNAs because it has transforming properties when expressed both in established cell lines such as Rat1 and NIH3T3 and in primary rat fibroblasts (13).…”

mentioning

confidence: 99%

A Novel Nuclear Export Signal and a REF Interaction Domain Both Promote mRNA Export by the Epstein-Barr Virus EB2 Protein

Hiriart¹,

Farjot

Gruffat

et al. 2003

Journal of Biological Chemistry

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105

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A striking characteristic of mRNA export factors is that they shuttle continuously between the cytoplasm and the nucleus. This shuttling is mediated by specific factors interacting with peptide motifs called nuclear export signals (NES) and nuclear localization signals. We have identified a novel CRM-1-independent transferable NES and two nuclear localization signals in the Epstein-Barr virus mRNA export factor EB2 (also called BMLF1, Mta, or SM) localized at the N terminus of the protein between amino acids 61 and 146. We have also found that a previously described double NES (amino acids 213-236) does not mediate the nuclear shuttling of EB2, but is an interaction domain with the cellular export factor REF in vitro. This newly characterized REF interaction domain is essential for EB2-mediated mRNA export. Accordingly, in vivo, EB2 is found in complexes containing REF as well as the cellular factor TAP. However, these interactions are RNase-sensitive, suggesting that the RNA is an essential component of these complexes.In cells infected by human herpesviruses, viral mRNAs and proteins are trafficked through the nuclear pore complex. Several cellular factors that mediate the nucleocytoplasmic transport of mRNAs have now been identified (1-6). Interestingly, some human herpesviruses carry, in their genome, genes whose products are also mRNA export factors, such as HSV-1 1 ICP27 (7) and the EBV BMLF1 early gene product originally called EB2 (8), but later called Mta (9) or SM (10). Such genes are conserved among all human herpesviruses, suggesting a conserved function for their products. At least for HSV-1 and EBV, the inactivation of ICP27 (11) or EB2 (12), respectively, abolishes the production of infectious viral particles, demonstrating that ICP27 and EB2 are essential factors for viral mRNA export and that their function cannot be trans-complemented by cellular factors. Moreover, EB2 appears to have an effect on cellular mRNAs because it has transforming properties when expressed both in established cell lines such as Rat1 and NIH3T3 and in primary rat fibroblasts (13).Most of the HSV-1 and EBV early and late mRNAs are transcribed from intronless genes. However, it is now clearly established that the nuclear export of mRNAs is dramatically increased when a splicing event occurs (14). In effect, splicing leads to the deposition on the mRNA of a multiprotein export complex (called EJC for exon-exon junction complex), including REF/Aly (Yra1 in yeast), Y14, RNPS1, SRm160, and Magoh, 20 -24 nucleotides upstream of the exon-exon junction (2-5). Such a complex is thought to export mRNAs by recruiting TAP/Mex67p (15) to cellular messenger RNPs (16 -18). For cellular mRNAs generated from intronless genes, they are likely to be exported to the cytoplasm by cellular factors through nonspecific interactions with mRNA-bound adapters like REF (19) or through sequence-specific interactions with SRp20 or 9G8 (20) or U2AF (21). It is therefore tempting to speculate that EB2, like its HSV-1 functional homolog ICP27 (7), is an...

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“…Furthermore, EB2 has been shown to be essential for the production of infectious viral particles [45] and for the nuclear export of most, but not all, late mRNAs produced from genes implicated in the capsid assembly and maturation [46].…”

Section: Their Functions In the Rna Exportmentioning

confidence: 99%

The Varicella-Zoster virus IE4 protein: A conserved member of the herpesviral mRNA export factors family and a potential alternative target in antiherpetic therapies

Ote

Piette

Sadzot-Delvaux

2010

Biochemical Pharmacology

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Epstein-Barr Virus mRNA Export Factor EB2 Is Essential for Production of Infectious Virus

Cited by 78 publications

References 51 publications

Spironolactone blocks Epstein–Barr virus production by inhibiting EBV SM protein function

Spironolactone blocks Epstein–Barr virus production by inhibiting EBV SM protein function

A Novel Nuclear Export Signal and a REF Interaction Domain Both Promote mRNA Export by the Epstein-Barr Virus EB2 Protein

The Varicella-Zoster virus IE4 protein: A conserved member of the herpesviral mRNA export factors family and a potential alternative target in antiherpetic therapies

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