Abstract
It is known that viruses can active the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway in host cells to support cell survival and viral replication; however, the role of PI3K/Akt signaling in the pathogenic mechanisms induced by Marek’s disease virus (MDV) which causes a neoplastic Marek’s disease in poultry, remains unknown. In this study, we showed that MDV activated the PI3K/Akt pathway in chicken embryo fibroblasts (CEFs) at the early phase of infection, whereas treatment with a PI3K inhibitor LY294002 prior to MDV infection decreased viral replication and DNA synthesis. Flow cytometry analysis showed that inhibition of the PI3K/Akt pathway could significantly increase apoptosis in MDV-infected host cells, indicating that activation of PI3K/Akt signaling could facilitate viral replication through support of cell survival during infection. Evaluation of the underlying molecular mechanism by co-immunoprecipitation and laser confocal microscopy revealed that a viral protein Meq interacted with both p85α and p85β regulatory subunits of PI3K and could induce PI3K/Akt signaling in Meq-overexpressing chicken fibroblasts. Our results showed, for the first time, that MDV activated PI3K/Akt signaling in host cells through interaction of its Meq protein with the regulatory p85 subunit of PI3K to delay cell apoptosis and promote viral replication. This study provides clues for further studies of the molecular mechanisms underlying MDV infection and pathogenicity for the host.
Highlights
Marek’s disease (MD) is caused by Marek’s disease virus (MDV), a highly oncogenic cell-associated α-herpesvirus inducing T-cell lymphoma, immunosuppression, and neurological disorders in poultry (Jarosinski et al, 2006)
To determine whether MDV could activate the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, chicken embryo fibroblasts (CEFs) were infected with MDV strains Md5, LZ1309, or 814 at 0.1 multiplicity of infection (MOI) and analyzed for Akt phosphorylation at different time points over 60 h post infection
GSK-3β and mTOR are known to be closely involved in apoptosis and oncogenesis (Mancinelli et al, 2017; Guri et al, 2018), our findings suggest that activation of the PI3K/Akt pathway plays an important role in the establishment and pathogenesis of MDV infection
Summary
Marek’s disease (MD) is caused by Marek’s disease virus (MDV), a highly oncogenic cell-associated α-herpesvirus inducing T-cell lymphoma, immunosuppression, and neurological disorders in poultry (Jarosinski et al, 2006). Meq can form homodimers or heterodimers with the c-Jun oncoprotein (Qian et al, 1996; Kung et al, 2001) and induce the expression of anti-apoptotic genes associated with oncogenic transformation of host cells (Jarosinski et al, 2006). Meq interaction with carboxyl-terminal-binding protein (CtBP) via the PXDLS motif is critical for tumorigenesis but not for MDV replication in chickens (Brown et al, 2006). According to the results of ChIP-seq analysis, 549 genes are downregulated and 236 are upregulated in Meq-overexpressing DF-1 chicken fibroblast cell line (Subramaniam et al, 2013), indicating that many more genes are potentially targeted by Meq in host cells and these interactions should be investigated
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