Academic journal article Genetics

Modeling Early Epstein-Barr Virus Infection in Drosophila Melanogaster: The BZLF1 Protein

Academic journal article Genetics

Modeling Early Epstein-Barr Virus Infection in Drosophila Melanogaster: The BZLF1 Protein

Article excerpt

ABSTRACT

Epstein-Barr virus (EBV) is the causative agent of infectious mononucleosis and is associated with several forms of cancer, including lymphomas and nasopharyngeal carcinoma. The EBV immediate-early protein BZLF1 functions as a transcriptional activator of EBV early gene expression and is essential for the viral transition between latent and lytic replication. In addition to its role in the EBV life cycle, BZLF1 (Z) also has profound effects upon the host cellular environment, including disruption of cell cycle regulation, signal transduction pathways, and transcription. In an effort to understand the nature of Z interactions with the host cellular environment, we have developed a Drosophila model of early EBV infection, where we have expressed Z in the Drosophila eye. Using this system, we have identified a highly conserved interaction between the Epstein-Barr virus Z protein and shaven, a Drosophila homolog of the human Pax2/5/8 family of genes. Pax5 is a well-characterized human gene involved with B-cell development. The B-cell-specific Pax5 also promotes the transcription of EBV latent genes from the EBV Wp promoter. Our work clearly demonstrates that the Drosophila system is an appropriate and powerful tool for identifying the underlying genetic networks involved in human infectious disease.

EPSTEIN-BARR virus (EBV) is a ubiquitous herpesvirus, having infected most of the world's adult population. Primary infection with EBV may result in infectious mononucleosis and predisposes certain individuals to cancer (ZuR HAUSEN et al. 1970; RICKINSON and KIEFF 2001). EBV infects mainly two cell types: epithelial cells, where it undergoes lytic replication, and B cells, where it initially replicates in a lytic manner before it enters a latent or dormant state (RiCKiNSON and KIEFF 2001). B cells normally may differentiate into plasma cells, which secrete Ig, or memory B cells (CALAME et al. 2003). During EBV lytic replication in B cells, the B cells have been shown to enter a plasma cell differentiation pathway (NIEDOBITEK et al. 1997), yet EBV persists in its latent form in memory B cells (BABCOCK et al. 1998), indicating that the virus takes advantage of B-cell differentiation pathways to efficiently replicate and maintain the virus.

EBV replication is dependent upon its host's cellular environment; hence the virus encodes proteins that interact with and alter the function of cellular proteins, thus altering the intracellular environment to suit the virus. One such EBV protein is BZLF1, an immediateearly protein expressed during lytic replication. BZLF1 (Z) is a transcriptional activator that binds to and activates the promoters of early EBV genes (CHEVALLIERGRECO et al. 1986; KENNEY et al. 1989; Cox et al. 1990; HoLLEY-GuTHRiE et al. 1990; GIOT el al. 1991; QUINLIVAN el al. 1993). The DNA-binding domain of Z bears homology to the API site binding proteins cjun and c-Fos (FARRELL el al. 1989). Therefore, Z is able to bind to API and API-like sites, which are present in the promoters of the EBV early genes (URIER el al. 1989; KIEFF and RICKINSON 2001). A loss of Z DNA-binding ability, such as with the Z mutant Z311 (GiOT et al. 1991), leads to a loss of Z transactivation function and prevents EBV lytic replication from occurring (GiOT el al. 1991).

BZLF1 has also been shown to interact with and/or modify the function of several key cellular proteins, including p53, promyelocytic leukemia protein (PML), CREB-binding protein (CBP), NF-êÂ, and signal transduction proteins such as the p38 and c-Jun N-terminal kinases (ADAMSON el al. 2000; ADAMSON and KENNEY 2001; reviewed in SINCLAIR 2003). BZLF1 physically associates with the p53 protein, and this interaction has been shown to prevent p53 from activating p53responsive promoters (ZHANG el al. 1994; MAUSER el al. 2002b). In addition, overexpression of p53 prevents BZLF1 transactivation of EBV early promoters (ZHANG el al. 1994). BZLF1 also physically associates with the p65 subunit of NF-êÂ, and this association was found to inhibit EBV lytic replication (GuTSCH et al. …

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