Abstract
Marek’s disease virus (MDV) is a potent oncogenic alphaherpesvirus that elicits a rapid onset of malignant T-cell lymphomas in chickens. Three MDV types, including GaHV-2 (MDV-1), GaHV-3 (MDV-2) and MeHV-1 (HVT), have been identified and all encode a US3 protein kinase. MDV-1 US3 is important for efficient virus growth in vitro. To study the role of US3 in MDV replication and pathogenicity, we generated an MDV-1 US3-null virus and chimeric viruses by replacing MDV-1 US3 with MDV-2 or HVT US3. Using MD as a natural virus-host model, we showed that both MDV-2 and HVT US3 partially rescued the growth deficiency of MDV-1 US3-null virus. In addition, deletion of MDV-1 US3 attenuated the virus resulting in higher survival rate and lower MDV specific tumor incidence, which could be partially compensated by MDV-2 and HVT US3. We also identified chicken histone deacetylase 1 (chHDAC1) as a common US3 substrate for all three MDV types while only US3 of MDV-1 and MDV-2 phosphorylate chHDAC2. We further determined that US3 of MDV-1 and HVT phosphorylate chHDAC1 at serine 406 (S406), while MDV-2 US3 phosphorylates S406, S410, and S415. In addition, MDV-1 US3 phosphorylates chHDAC2 at S407, while MDV-2 US3 targets S407 and S411. Furthermore, biochemical studies show that MDV US3 mediated phosphorylation of chHDAC1 and 2 affect their stability, transcriptional regulation activity, and interaction network. Using a class I HDAC specific inhibitor, we showed that MDV US3 mediated phosphorylation of chHDAC1 and 2 is involved in regulation of virus replication. Overall, we identified novel substrates for MDV US3 and characterized the role of MDV US3 in MDV pathogenesis.
Highlights
Marek’s disease virus (MDV), an avian alphaherpesvirus, is the etiological agent of Marek’s disease (MD) which is associated with rapid induction of T-cell lymphomas in chickens
We evaluated the importance of MDV US3 in regulating MDV replication and pathogenesis in chickens
We identified chicken histone deacetylase 1 and 2 as novel substrates of US3 for MDV and characterized the potential impacts of MDV US3 induced phosphorylation in their protein stability, transcriptional regulation and protein interactions; to our knowledge, this is the first comparative study of the functions of US3 from all three MDV types
Summary
Marek’s disease virus (MDV), an avian alphaherpesvirus, is the etiological agent of Marek’s disease (MD) which is associated with rapid induction of T-cell lymphomas in chickens. Three antigenically related MDVs have been identified and sequenced, including MDV1 ( known as Gallid alphaherpesvirus 2 [GaHV-2]), MDV-2 ( known as Gallid alphaherpesvirus 3 [GaHV-3]), and turkey herpesvirus (HVT; known as Meleagrid alphaherpesvirus type 1 [MeHV-1]) [1]. MDV-1 can cause tumors in infected chickens, while MDV2 and HVT are naturally non-oncogenic viruses from chickens and turkeys, respectively. Attenuated MDV-1 along with MDV-2 and HVT have been used, alone or in combination, as vaccines to protect susceptible chickens from MD. Most MDV-1 genes have homologues in other alphaherpesviruses and share similar functions, but MDV encodes some unique genes such as meq and vTR which are directly involved in MDV oncogenicity [3,4]
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