Research Summary

Understanding the Molecular Crosstalk between Unfolded Protein Response and EBV pathogenesis in developing B-cell Lymphomas

Epstein-Barr virus (EBV) is associated with several B-cell lymphomas development. In-vitro, EBV can readily transform quiescent B-cells into continuously proliferating lymphoblastoid cell-lines (LCLs), which express only a subset of latent-genes. EBNA3C, one of the essential latent-genes expressed in transformed B-cells, deregulates many important cellular pathways like cell-cycle checkpoints, apoptosis and ubiquitin-proteasome degradation pathway, which results in aberrant cell-proliferation. Cancer-cells often suffer ER-mediated unfolded-protein-response (UPR)-stress due to uncontrolled cell-proliferation and high metabolic-demand and initiate autophagy for scavenging the damaged organelle and protein-aggregates. Tumor-viruses, including EBV were shown to modulate UPR-autophagy network as a survival-strategy. However, the mechanisms that connect regulators of this network with EBV-induced B-cell transformation and consequently B-cell lymphomas development remain unclear. Here we propose that EBNA3C given its capacity to integrate diverse signaling-networks may also target UPR-autophagy pathway for B-cell transformation and subsequent lymphoma development. The study aims to identify key-players of deregulated UPR-autophagy cascade in response to EBV-infection and EBNA3C-expression and to delineate the functional significance of EBV-mediated deactivation of tumor-suppressors activities particularly in DNA-damage-response pathway to regulate UPR-autophagy mechanism. The prominent interaction of EBNA3C with the protein-degradation pathway led us to hypothesize that EBNA3C may also be involved in regulating autophagy-lysosomal mediated degradation of protein-aggregates.

Figure Legend: "Targeting unfolded protein response (UPR)-autophagy network offers a promising therapeutic option for many human cancers."