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Evidence for modulation of BAG3 by JC virus early protein

¹ Temple University/University of Salerno;
² Temple University;
³ University of Salerno

⁴ E-mail: kamel.khalili{at}temple.edu

Polyomavirus JC (JCV) infects oligodendrocytes and astrocytes in the brain and is the cause of the demyelinating disease, progressive multifocal leukoencephalopathy (PML). In cell culture, JCV infection is characterized by severe damage to cellular DNA, which begins early in infection and a viral cytopathic effect, which is observed late in infection. Nevertheless, these JCV-infected cells show a low level of apoptosis, at both the early and late stages of infection. This suggests that there is a conflicting interplay between viral anti-apoptotic pathways that seek to optimize virus production, e.g., through T-antigen/p53 interaction, and cellular pro-apoptotic pathways that seek to eliminate virally infected cells. The apoptosis regulatory protein BAG3 is a member of the human Bcl-2 associated athanogene (BAG) family of proteins, which function as molecular co-chaperones through its interaction with Hsc70/Hsp70 and functions in the regulation of the cellular stress response, proliferation and apoptosis. We now report that BAG3 protein is downregulated upon JCV infection and that this effect is mediated by JCV T-antigen (T-Ag) via repression of the BAG3 promoter. The site of action of T-Ag was mapped to an AP2 site in the BAG3 promoter and gel shift and ChIP assays showed that T-Ag inhibited AP2 binding to this site resulting in downregulation of BAG3 promoter expression. Using BAG3 and T-Ag expression and BAG3 siRNA, we found that BAG3 and T-Ag had antagonistic effects on the induction of apoptosis, being anti-apoptotic and pro-apoptotic respectively. The significance of these interactions to the JCV life cycle is discussed.

Received 10 November 2008; accepted 8 March 2009.