Tumor suppressor reprogramming by EBV through post-translational modification

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Abstract: Immunocompromised HIV-positive patients have serious complications with opportunistic oncogenic viral infections that can lead B-cell lymphomas. Epstein-Barr virus (EBV) and Kaposi’s sarcoma associated virus (KSHV) are two human oncogenic gammaherpesviruses associated with B-cell lymphomas either individually or as co-infections. EBV-associated B-cell lymphomas are established as latency III infection with the major latent genes expressed as well as the small non-coding RNAs. EBV transformed B cells drive latency III, also seen in HIV associated EBV-positive lymphomas. EBV is also associated with other lymphomas including Burkitt’s lymphoma, Hodgkin’s and non-Hodgkin’s lymphoma, and post-transplant and AIDS associated lymphomas in immunocompromised HIV-patients. EBV also efficiently transforms human primary B-cells in vitro, into immortalized lymphoblastoid cell lines (LCLs). These nascent transformed B cells express latent genes, one of which is the Epstein-Barr nuclear antigen EBNA3C, essential for immortalization of B-cells. EBNA3C regulates cellular and viral gene expression through interaction with transcription repressors, and complexes of the mammalian cell cycle which include CyclinA, and components of the SCF proteosome degradation pathway. Our long term goal is to determine the role of EBNA3C in reprogramming viral and infected cell genomes through interactions with the tumor suppressor Rb and the regulatory consequences of these interactions as related to cell survival, cell cycle regulation and proliferation. We will investigate the mechanism of Rb regulation through specific post- translation modifications after infection by EBV, which includes phosphorylation and acetylation important for targeted ubiquitination. We will determine if enhanced phosphorylation/acetylation of Rb occurs through recruitment of CyclinD/Cdk4/6 complexes by EBNA3C important for cell cycle progression. This results in loss of Rb through ubiquitination which leads to cell and viral genome reprogramming by activation of the cellular E2F pathway, cell cycle progression, increased survival and malignant transformation. These studies will examine the role of EBNA3C in regulating the Rb/CyclinD/E2F network important for B-cell immortalization with implications for novel insights into KSHV and EBV contributions to latency III lymphomas in HIV patients.