Divergent roles of nonsense-mediated RNA decay in oncovirus latency and reactivation

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Nonsense-mediated RNA Decay (NMD) is a highly conserved cellular quality control pathway that degrades many mutant or aberrantly spliced RNA transcripts. Reports in the literature have recently linked NMD processes to oncogenesis and metastasis, in complex and sometimes contradictory ways. Often considered a tumor suppressor pathway, NMD is frequently downregulated in cancers, resulting in higher expression of (sometimes mutated) oncogenes. On the other hand, some cancers appear to harness or even enhance the NMD system to degrade transcripts of tumor suppressor genes, dysregulating oncogene expression and leading to increased cancer cell proliferation. EBV is a ubiquitous human pathogen that infects more than 90% of the world’s population and is associated with cancers including lymphomas, gastric carcinoma and nasopharyngeal carcinoma. Typically, EBV persists in host B cells in a latent phase, during which time limited viral gene expression shields the virus from the host immune system. Periodically, reactivation of the lytic cycle leads to viral takeover of the host cell and production of new infectious virions, facilitating viral spread. Interestingly, some EBV RNA transcripts expressed during reactivation appear to be NMD targets. Our preliminary studies have revealed that EBV actively inhibits host cellular NMD during lytic reactivation, presumably preventing degradation of viral RNA transcripts and facilitating viral protein translation and virion production. In contrast, we find that the NMD pathway is active during the latency phase where it likely promotes cell proliferation while simultaneously preventing lytic reactivation. These two opposite modes of engagement form a sort of “yin and yang” relationship between EBV and host NMD that plays a key role in governing its biphasic infection strategy. With this project we will investigate this novel dynamic viral interface with a host system to determine the mechanistic underpinnings of EBV-NMD interactions and determine its functional impact on viral reactivation, viral latency and lymphoma cell growth and proliferation.