ICP27 protein of Marek’s disease virus interacts with SR proteins and inhibits the splicing of cellular telomerase chTERT and viral vIL8 transcripts

Amor, Souheila; Strassheim, Swantje; Dambrine, Ginette; Rémy, Sylvie; Rasschaert, Denis; Laurent, Sylvie

doi:10.1099/vir.0.028969-0

Cited by 22 publications

(19 citation statements)

References 28 publications

(47 reference statements)

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“…but consistent with Western blot results, 3ϫFlag further enhanced detection. MDV ICP27 was predominantly seen in the nucleus regardless of the epitope or terminal tag, similar to what has been observed previously (41). These results show that addition of N-or C-terminal epitope tags to ICP27 did not reduce the ability of MDV to replicate in cell culture and these tags, in particular 3ϫFlag, can be used for identification of MDV ICP27.…”

Section: Figsupporting

confidence: 88%

TheHerpesviridaeConserved Multifunctional Infected-Cell Protein 27 (ICP27) Is Important but Not Required for Replication and Oncogenicity of Marek’s Disease Alphaherpesvirus

Ponnuraj

Tien

Vega-Rodriguez

et al. 2019

J Virol

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The Herpesviridae conserved infected-cell protein 27 (ICP27) is essential for cell culture-based replication of most herpesviruses studied. For members of the Alphaherpesvirinae, ICP27 regulates the expression of many viral genes, including expression of pUL44 (gC), pUL47 (VP13/14), and pUL48 (VP16). These three viral proteins are dysregulated during Marek’s disease alphaherpesvirus (MDV) replication in cell culture. MDV replicates in a highly cell-associated manner in cell culture, producing little to no infectious virus. In contrast, infectious cell-free MDV is produced in specialized feather follicle epithelial (FFE) cells of infected chickens, in which these three genes are abundantly expressed. This led us to hypothesize that MDV ICP27, encoded by gene UL54, is a defining factor for the dysregulation of gC, pUL47, and pUL48 and, ultimately, ineffective virus production in cell culture. To address ICP27’s role in MDV replication, we generated recombinant MDV with ICP27 deleted (vΔ54). Interestingly, vΔ54 replicated, but plaque sizes were significantly reduced compared to those of parental viruses. The reduced cell-to-cell spread was due to ICP27 since plaque sizes were restored in rescued viruses, as well as when vΔ54 was propagated in cells expressing ICP27 in trans. In chickens, vΔ54 replicated, induced disease, and was oncogenic but was unable to transmit from chicken to chicken. To our knowledge, this is the first report showing that the Herpesviridae conserved ICP27 protein is dispensable for replication and disease induction in its natural host. IMPORTANCE Marek’s disease (MD) is a devastating oncogenic disease that affects the poultry industry and is caused by MD alphaherpesvirus (MDV). Current vaccines block induction of disease but do not block chicken-to-chicken transmission. There is a knowledge gap in our understanding of how MDV spreads from chicken to chicken. We studied the Herpesviridae conserved ICP27 regulatory protein in cell culture and during MDV infection in chickens. We determined that MDV ICP27 is important but not required for replication in both cell culture and chickens. In addition, MDV ICP27 was not required for disease induction or oncogenicity but was required for chicken-to-chicken transmission. This study is important because it addresses the role of ICP27 during infection in the natural host and provides important information for the development of therapies to protect chickens against MD.

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Section: Figsupporting

confidence: 88%

TheHerpesviridaeConserved Multifunctional Infected-Cell Protein 27 (ICP27) Is Important but Not Required for Replication and Oncogenicity of Marek’s Disease Alphaherpesvirus

Ponnuraj

Tien

Vega-Rodriguez

et al. 2019

J Virol

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“…Despite this general pattern, we did identify a minority of candidate ORFs with mutations that appeared to be associated specifically with virulent MDV strains (Table 2) including the general transactivators Meq (MDV076), ICP4 (MDV084), and ICP27 (MDV068). Several of the listed genes have been shown experimentally to play a role in MDV pathogenicity (Amor et al, 2011;Brown et al, 2006;Jarosinski, Osterrieder, Nair, & Schat, 2005;Kamil et al, 2005;Liu et al, 1999;Lupiani et al, 2004;Nair, 2013;Reddy et al, 2002;Tischer, Schumacher, Messerle, Wagner, & Osterrieder, 2002). While known as an important MDV oncoprotein, Meq is also expressed during lytic replication and has a potential role in the rapid production of virus progeny (Coupeau, Dambrine, & Rasschaert, 2012).…”

Section: Discussionmentioning

confidence: 99%

A phylogenomic analysis of Marek's disease virus reveals independent paths to virulence in Eurasia and North America

Trimpert

Groenke

Jenckel

et al. 2017

Evolutionary Applications

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Virulence determines the impact a pathogen has on the fitness of its host, yet current understanding of the evolutionary origins and causes of virulence of many pathogens is surprisingly incomplete. Here, we explore the evolution of Marek's disease virus (MDV), a herpesvirus commonly afflicting chickens and rarely other avian species. The history of MDV in the 20th century represents an important case study in the evolution of virulence. The severity of MDV infection in chickens has been rising steadily since the adoption of intensive farming techniques and vaccination programs in the 1950s and 1970s, respectively. It has remained uncertain, however, which of these factors is causally more responsible for the observed increase in virulence of circulating viruses. We conducted a phylogenomic study to understand the evolution of MDV in the context of dramatic changes to poultry farming and disease control. Our analysis reveals evidence of geographical structuring of MDV strains, with reconstructions supporting the emergence of virulent viruses independently in North America and Eurasia. Of note, the emergence of virulent viruses appears to coincide approximately with the introduction of comprehensive vaccination on both continents. The time‐dated phylogeny also indicated that MDV has a mean evolutionary rate of ~1.6 × 10−5 substitutions per site per year. An examination of gene‐linked mutations did not identify a strong association between mutational variation and virulence phenotypes, indicating that MDV may evolve readily and rapidly under strong selective pressures and that multiple genotypic pathways may underlie virulence adaptation in MDV.

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“…MDV also contains a homologue of ICP27 (58) and the protein was shown to interact with SR proteins and inhibit splicing (59). Therefore, the hypothetical role of p012 in splicing and/or mRNA export remains to be addressed.…”

Section: Discussionmentioning

confidence: 99%

The ORF012 Gene of Marek's Disease Virus Type 1 Produces a Spliced Transcript and Encodes a Novel Nuclear Phosphoprotein Essential for Virus Growth

Schippers

Jarosinski

Osterrieder

2015

J Virol

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Marek's disease virus (MDV) causes a devastating oncogenic disease in chickens with high morbidity and mortality. The costs for disease prevention reach several billion dollars annually. The functional investigation of MDV genes is necessary to understand its complex replication cycle, which eventually could help us to interfere with MDV and herpesviral pathogenesis. We have identified a previously unidentified phosphoprotein encoded by MDV ORF012. We were able to show experimentally that predicted splicing of the gene based on bioinformatics data does indeed occur during replication. The newly identified p012 is essential for MDV replication and localizes to the nucleus due to the presence of a transferable nuclear localization signal at its C terminus. Our results also imply that p012 could constitute a nucleocytoplasmic shuttle protein, a feature that could prove interesting and important.

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ICP27 protein of Marek’s disease virus interacts with SR proteins and inhibits the splicing of cellular telomerase chTERT and viral vIL8 transcripts

Cited by 22 publications

References 28 publications

TheHerpesviridaeConserved Multifunctional Infected-Cell Protein 27 (ICP27) Is Important but Not Required for Replication and Oncogenicity of Marek’s Disease Alphaherpesvirus

TheHerpesviridaeConserved Multifunctional Infected-Cell Protein 27 (ICP27) Is Important but Not Required for Replication and Oncogenicity of Marek’s Disease Alphaherpesvirus

A phylogenomic analysis of Marek's disease virus reveals independent paths to virulence in Eurasia and North America

The ORF012 Gene of Marek's Disease Virus Type 1 Produces a Spliced Transcript and Encodes a Novel Nuclear Phosphoprotein Essential for Virus Growth

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