title: Bag3-induced autophagy is associated with degradation of JCV oncoprotein, T-Ag.
abstract: JC virus, JCV, is a human neurotropic polyomavirus whose replication in glial cells causes the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML). In addition, JCV possesses oncogenic activity and expression of its transforming protein, large T-antigen (T-Ag), in several experimental animals induces tumors of neural origin. Further, the presence of JCV DNA and T-Ag have been repeatedly observed in several human malignant tissues including primitive neuroectodermal tumors and glioblastomas. Earlier studies have demonstrated that Bag3, a member of the Bcl-2-associated athanogene (Bag) family of proteins, which is implicated in autophagy and apoptosis, is downregulated upon JCV infection of glial cells and that JCV T-Ag is responsible for suppressing the activity of the BAG3 promoter. Here, we investigated the possible impact of Bag3 on T-Ag expression in JCV-infected human primary glial cells as well as in cells derived from T-Ag-induced medulloblastoma in transgenic animals. Results from these studies revealed that overexpression of Bag3 drastically decreases the level of T-Ag expression by inducing the autophagic degradation of the viral protein. Interestingly, this event leads to the inhibition of JCV infection of glial cells, suggesting that the reduced levels of T-antigen seen upon the overexpression of Bag3 has a biological impact on the viral lytic cycle. Results from protein-protein interaction studies showed that T-Ag and Bag3 physically interact with each other through the zinc-finger of T-Ag and the proline rich domains of Bag3, and this interaction is important for the autophagic degradation of T-Ag. Our observations open a new avenue of research for better understanding of virus-host interaction by investigating the interplay between T-Ag and Bag3, and their impact on the development of JCV-associated diseases.
authors.affiliation: Department of Neuroscience and Center for Neurovirology Temple University School of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Ilker Kudret
authors.initials: IK
authors.lastname: Sariyer
authors.forename: Nana
authors.initials: N
authors.lastname: Merabova
authors.forename: Prem Kumer
authors.initials: PK
authors.lastname: Patel
authors.forename: Tijana
authors.initials: T
authors.lastname: Knezevic
authors.forename: Alessandra
authors.initials: A
authors.lastname: Rosati
authors.forename: Maria C
authors.initials: MC
authors.lastname: Turco
authors.forename: Kamel
authors.initials: K
authors.lastname: Khalili
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism / Q000821:virology; D001343:Autophagy; D001665:Binding Sites; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004279:DNA, Viral / Q000235:genetics; D018628:Gene Dosage; D054884:Host-Pathogen Interactions; D006801:Humans; D007577:JC Virus / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D059748:Proteolysis; D034622:RNA Interference; D014407:Tumor Cells, Cultured
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000952:Antigens, Polyomavirus Transforming; D051017:Apoptosis Regulatory Proteins; C414431:BAG3 protein, human; D004279:DNA, Viral