PMID:21325409

Citation	Hagemeier, SR, Barlow, EA, Kleman, AA and Kenney, SC (2011) The Epstein-Barr virus BRRF1 protein, Na, induces lytic infection in a TRAF2- and p53-dependent manner. J. Virol. 85:4318-29
Abstract	The Epstein-Barr virus (EBV) BRRF1 lytic gene product (Na) is encoded within the same immediate-early region as the BZLF1 (Z) and BRLF1(R) gene products, but its role during EBV infection has not been well defined. We previously showed that Na cooperates with the R protein to induce lytic gene expression in latently infected EBV-positive 293 cells, and in some EBV-negative cell lines it can activate the Z promoter in reporter gene assays. Here we show that overexpression of Na alone is sufficient to induce lytic gene expression in several different latently infected epithelial cell lines (Hone-Akata, CNE2-Akata, and AGS-Akata), while knockdown of endogenous Na expression reduces lytic gene expression. Consistent with its ability to interact with tumor necrosis factor receptor-associated factor 2 (TRAF2) in a yeast two-hybrid assay, we demonstrate that Na interacts with TRAF2 in cells. Furthermore, we show that TRAF2 is required for Na induction of lytic gene expression, that Na induces Jun N-terminal protein kinase (JNK) activation in a TRAF2-dependent manner, and that a JNK inhibitor abolishes the ability of Na to disrupt viral latency. Additionally, we show that Na and the tumor suppressor protein p53 cooperate to induce lytic gene expression in epithelial cells (including the C666-1 nasopharyngeal carcinoma cell line), although Na does not appear to affect p53 function. Together these data suggest that Na plays an important role in regulating the switch between latent and lytic infection in epithelial cells and that this effect requires both the TRAF2 and p53 cellular proteins.
Links	PubMed PMC3126225 Online version:10.1128/JVI.01856-10
Keywords	Cell Line; Cell Survival; Herpesvirus 4, Human/growth & development; Herpesvirus 4, Human/pathogenicity; Humans; Protein Binding; Protein Interaction Mapping; TNF Receptor-Associated Factor 2/metabolism; Tumor Suppressor Protein p53/metabolism
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
EBVB9:BRRF1		GO:0019046: release from viral latency	ECO:0000315:		P		Figure 1 A-C: Three different cell lines were transfected with plasmids for the over-expression of Na (which is the product of gene BRRF1) as well as control plasmids with no over-expression of Na. To see if Na initiated lysis in the cells in which Na was overproduced, immunoassays were performed to search for lytic cell products. The proteins searched for include BMRF1, Z protein, R protein, Na (through FLAG), and β-actin. In all three types of cells with plasmids over-expressing BRRF1, these lytic proteins were found in a greater amount than in the cells without the over-expression plasmids. Expression of BRRF1 leads to a product that affects maintenance of viral latency. The evidence code is IMP because there is over-expression of the gene. Presence of the gene product resulted in an increase in specific lytic proteins measured by an immunoblot assay.	complete CACAO 7262
EBVB9:BRRF1	involved_in	GO:0019046: release from viral latency	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
EBVB9:RTA		GO:0019046: release from viral latency	ECO:0000315:		P		Figure 1 A-C: Three different cell lines were transfected with plasmids for the over-expression of Na (which is the product of gene BRRF1) as well as control plasmids with no over-expression of Na. To see if Na initiated lysis in the cells in which Na was overproduced, immunoassays were performed to search for lytic cell products. The proteins searched for include BMRF1, Z protein, R protein, Na (through FLAG), and β-actin. In all three types of cells with plasmids over-expressing BRRF1, these lytic proteins were found in a greater amount than in the cells without the over-expression plasmids. Expression of BRRF1 leads to a product that affects maintenance of viral latency. The evidence code is IMP because there is over-expression of the gene. Presence of the gene product resulted	complete CACAO 9669

References

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