title: Activation of TRAF5 and TRAF6 signal cascades negatively regulates the latent replication origin of Epstein-Barr virus through p38 mitogen-activated protein kinase.
abstract: Latent Epstein-Barr virus (EBV) is maintained by the virus replication origin oriP that initiates DNA replication with the viral oriP-binding factor EBNA1. However, it is not known whether oriP's replicator activity is regulated by virus proteins or extracellular signals. By using a transient replication assay, we found that a low level of expression of viral signal transduction activator latent membrane protein 1 (LMP1) suppressed oriP activity. The binding site of the tumor necrosis factor receptor-associated factor (TRAF) of LMP1 was essential for this suppressive effect. Activation of the TRAF signal cascade by overexpression of TRAF5 and/or TRAF6 also suppressed oriP activity. Conversely, blocking of TRAF signaling with dominant negative mutants of TRAF5 and TRAF6, as well as inhibition of a downstream signal mediator p38 MAPK, released the LMP1-induced oriP suppression. Furthermore, activation of TRAF6 signal cascade by lipopolysaccharides (LPS) resulted in loss of EBV from Burkitt's lymphoma cell line Akata, and inhibition of p38 MAPK abolished the suppressive effect of LPS. These results suggested that the level of oriP activity is regulated by LMP1 and extracellular signals through TRAF5- and TRAF6-mediated signal cascades.
authors.affiliation: Department of Tumor Virology, Division of Virology and Immunology, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo, Tokyo 113-8510, Japan. shirakata.creg@mri.tmd.ac.jp
authors.forename: M
authors.initials: M
authors.lastname: Shirakata
authors.forename: K I
authors.initials: KI
authors.lastname: Imadome
authors.forename: K
authors.initials: K
authors.lastname: Okazaki
authors.forename: K
authors.initials: K
authors.lastname: Hirai
mesh_terms: D001665:Binding Sites; D002051:Burkitt Lymphoma; D002213:Capsid; D002461:Cell Line, Transformed; D004261:DNA Replication; D015536:Down-Regulation; D006367:HeLa Cells; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009154:Mutation; D010957:Plasmids; D011506:Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D048015:TNF Receptor-Associated Factor 5; D048029:TNF Receptor-Associated Factor 6; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D017735:Virus Latency; D014779:Virus Replication; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: C037662:EBV-associated membrane antigen, Epstein-Barr virus; D008070:Lipopolysaccharides; D011506:Proteins; D048015:TNF Receptor-Associated Factor 5; D048029:TNF Receptor-Associated Factor 6; D014763:Viral Matrix Proteins; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases