Evidence for modulation of BAG3 by polyomavirus JC early protein.
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 conflicting interplay between viral anti-apoptotic pathways that seek to optimize virus production, e.g. through T antigen (T-Ag)-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 their interaction with Hsc70/Hsp70 and function in the regulation of the cellular stress response, proliferation and apoptosis. This study showed that BAG3 protein is downregulated upon JCV infection and that this effect is mediated by JCV 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 chromatin immunoprecipitation 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, it was 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.
Basile
Anna
A
Department of Pharmaceutical Sciences, University of Salerno, via ponte don Melillo, 84084 Fisciano, Italy.|Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, 1900 North 12th Street, Philadelphia, PA 19122, USA.
Darbinian
Nune
N
Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, 1900 North 12th Street, Philadelphia, PA 19122, USA.
Kaminski
Rafal
R
Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, 1900 North 12th Street, Philadelphia, PA 19122, USA.
White
Martyn K
MK
Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, 1900 North 12th Street, Philadelphia, PA 19122, USA.
Gentilella
Antonio
A
Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, 1900 North 12th Street, Philadelphia, PA 19122, USA.
Turco
Maria Caterina
MC
Department of Pharmaceutical Sciences, University of Salerno, via ponte don Melillo, 84084 Fisciano, Italy.
Khalili
Kamel
K
Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, 1900 North 12th Street, Philadelphia, PA 19122, USA.
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis*; D000952:Antigens, Polyomavirus Transforming / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins; D001253:Astrocytes / Q000821:virology; D001665:Binding Sites; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation / Q000379:methods; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D050556:Fatty Acid-Binding Proteins / Q000037:antagonists & inhibitors; D005786:Gene Expression Regulation; D006801:Humans; D007577:JC Virus / Q000502:physiology*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012097:Repressor Proteins / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D000952:Antigens, Polyomavirus Transforming; D051017:Apoptosis Regulatory Proteins; C414431:BAG3 protein, human; C493410:FABP4 protein, human; D050556:Fatty Acid-Binding Proteins; D012097:Repressor Proteins