Transcriptional Activation of p62 by the master antioxidant NRF2 in EBV latency

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Project Summary EBV infection is associated with a panel of diseases and cancers, and serves as a fascinating paradigm for the study of host-virus interactions. Oxidative stress is essential for virus-mediated oncogenesis, and for EBV transformation of B cells. Reactive oxygen species (ROS) are independently induced by EBV-encoded products LMP1, EBNA1/2, and EBERs in EBV latency. Our most recent publication shows for the first time that the master antioxidant pathway Keap1-NRF2 is spontaneously activated in virus-transformed cells. With the support from the parent R15, we have shown recently that LMP1 induces p62 expression via NFκB and AP1 axes. In this supplementary project, we will test the hypothesis that EBV-produced ROS trigger the activation of the Keap1- NRF2 pathway that represents an equally important mechanism for p62 induction in EBV latency. The objective of this project is to address how the Keap1-NRF2 pathway is activated in EBV latency, and further define its role in p62 (and other targets) transcriptional activation, with the long-term goal to identify novel factors that regulate EBV-host interaction and may serve as potential context-specific targets for treating EBV-associated diseases and malignancies. The proximate expected outcome of this project is the definition of novel roles of the Keap1-NRF2 antioxidant defense in EBV latent infection. This study is significant in that disclosing how EBV controls the balance between oxidative stress and antioxidant defense will greatly improve our understanding of EBV latency and pathogenesis. Long-term pursuits may develop strategies by targeting these processes and their interaction with other cellular mechanisms for therapeutic applications.