Biology

Dr. Shuvomoy Banerjee
Amity University, Noida Campus New Delhi NCR

Tumor viruses have evolved unique strategies for modulating the expression of an array of cellular genes and signaling networks to enhance persistence, latency and survival of infected cells. Among them, gammaherpesviruses, specifically Epstein-Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV) are associated with a wide range of human malignancies. EBV latent antigen 3C (EBNA3C) is particularly essential for EBV-induced immortalization of B-cells. Interferon regulatory factors are key transcription factors of the IRF family that regulate diverse functions in B cell development. In our study, we demonstrated that EBNA3C can contribute to B-cell transformation by modulating the molecular interplay between cellular IRF4 and IRF8. Our work also revealed that EBNA3C stabilize IRF4, which leads to downregulation of IRF8 by enhancing its proteasome-mediated degradation. Interestingly, si-RNA mediated knock-down of endogenous IRF4 results significant reduction in proliferation of EBV-transformed lymphoblastoid cell lines (LCLs), as well as augmentation of DNA damage-induced apoptosis. These studies thus add a novel molecular link by which EBV deregulates cellular activities, through differential regulation of IRF4 and IRF8 activities increasing the potential for therapeutic intervention against EBV-associated cancers. Notably, the Moloney murine leukemia provirus integration site (PIM-1), which encodes an oncogenic serine/threonine kinase, is linked to vital cellular functions. Our comprehensive research explored the molecular mechanism by which EBNA3C enhances Pim-1 expression in EBV-infected primary B-cells. We demonstrated that EBNA3C physically associates with Pim-1 through its amino-terminal domain, and forms a molecular complex in B-cells. Moreover, EBNA3C stabilize Pim-1 through abrogation of the proteasome/Ubiquitin pathway to enhance Pim-1 mediated phosphorylation of p21 at Thr145 residue. Henceforth, our study not only describes the critical role of oncoprotein Pim-1 in EBV-mediated progression of lymphoma but also opens up novel insights into cellular oncogenic kinase-targeted therapeutic intervention in EBV-associated human malignancies. Like EBV, KSHV also directly influences T-lymphocyte activation via targeting the level of MHC-II expression. Particularly, Kaposi’s sarcoma-associated herpesvirus (KSHV) encoded LANA (latency associated nuclear antigen) is known to evade MHC-I peptide processing, however, the effect on MHC-II remained unclear. We reported that KSHV-LANA down-regulates MHC-II expression and presentation by inhibiting the transcription of MHC II transactivator (CIITA) promoter pIII and pIV in a dose-dependent manner. Henceforth, this particular study proved that LANA can evade MHC-II presentation and suppress CIITA transcription to provide the unique strategy of KSHV escape from immune surveillance by cytotoxic T-cells. Overall, our research helped to provide several lines of evidence as to the mechanisms of differential regulation of host factors during gammaherpesvirus-mediated oncogenesis and also to come up with potential approaches to therapeutically combat them.