Understanding the Role of Epstein Barr virus essential Nuclear antigen EBNA3C in regulating unfolding protein response UPR Autophagy network

Abstract

In rapidly proliferating cancer cells, endoplasmic reticulum (ER) tends to be overloaded with unfolded and misfolded proteins due to high metabolic demand. With the limited protein folding capacity of ER, cancer cells suffer from Unfolded Protein Response (UPR) stress and subsequently elevate autophagy, in which the protein-aggregates are degraded and provide free energy in form of amino acids allowing cancer cells for an uninterrupted proliferation. Consequently, several anticancer molecules targeting UPR-autophagy network are currently under clinical trials. Epstein-Barr virus (EBV) is associated with a number of B-cell lymphomas. EBV can readily transform quiescent B-lymphocytes into continuously proliferating lymphoblastoid cell lines (LCLs), providing an excellent model system for studying EBV associated B-cell lymphomagenesis. EBNA3C, one of the essential viral oncoproteins for B-cell transformation, manipulates multiple cell pathways – most strikingly cell-cycle/apoptosis and ubiquitin-targeted protein-degradation machineries. Interestingly, several components of these pathways were previously shown to be intricately connected with the UPR-autophagy network in the development of human malignancies. In our study, we have shown that EBNA3C transcriptionally upregulates several autophagy genes (ATG3, ATG5, and ATG7), particularly involved in autophagosome formation, under nutrient deprived conditions. EBNA3C recruits several histone activation epigenetic marks to regulate autophagy gene transcription. Moreover, EBNA3C specifically elevates PERK-eIF2α-ATF4 UPR signaling cascade in normal growth conditions, whereas in the presence of UPR-inducers it blocks further UPR activation, indicating EBNA3C promotes an adaptive condition for cell survival. Overall, our study provides a new role of an essential EBV oncoprotein in regulating autophagy-UPR cascade and offers novel targets for potential therapeutic expansion against multiple EBV induced B-cell lymphomas.