The Ubiquitin Sensor p62 Is A Novel Component of EBV LMP1 Signalosome

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Project Summary Epstein-Barr Virus (EBV), the first identified human cancer virus, is associated with a panel of malignancies of lymphocytic and epithelial origin, and serves as a paradigm for the study of host-virus interaction. EBV is well known to manipulate the host ubiquitin machinery to facilitate its latent persistence and oncogenesis, examplified by EBV LMP1 signal transduction to the activation of multiple transcription factors, such as NFκB and those we have identified including IRF7/IRF4, which control immune response and inflammation, as well as cell survival and growth. Constitutive and well balanced activation of LMP1 signaling is crucial for survival of EBV-transformed cells, and its depletion or overexpression leads to cell death. It is therefore vital to delineate the detailed mechanisms underlying LMP1 signal transduction for understanding EBV-mediated oncogenesis. p62 (also called SQSTM1, Sequestosome 1) is a ubiqutin sensor and a signal transducing adaptor that interacts with TRAF6 and facilitates the recruitment of ubiquitinated signal intermediators for the activation of NFκB in diverse contexts. In turn, p62 is induced by NFκB activity. EBV LMP1 is known to activate NFκB in its latency. However, the interaction between p62 and EBV latency has never been studied. We have recently published interesting and important results, which imply p62 in LMP1-mediated functions in EBV latency. We further show that p62 is upregulated in EBV latency 3, depending on LMP1/NFκB pathway activity, and that p62 interacts with LMP1 and shRNA-mediated p62 depletion in LCLs reduces cell proliferation. Thus, we hypothsize that EBV latent infection induces p62 expression through LMP1 signaling, and in turn, p62 participates in LMP1 signal transduction leading to NFκB activation. We propose to study: Aim 1. The transcriptional regulation of p62 by the LMP1/NFκB and LMP1/AP1 pathway axes; Aim 2. The role of p62 in LMP1 signaling to NFκB activation in EBV latency, including the underlying mechanisms, which include: a) p62-TRAF6 interaction; and b) p62 as a ubiquitin sensor that facilitates the recruitment of signal molecules. Findings from this study will identify p62 as a novel and critical player in EBV LMP1 signaling, and long-term pursuits may identify p62-mediated functions as a potential therapeutic target for EBV-associated malignancies. This proposal involves a series of techniques spanning different biomedical disciplines, which provide an excellent training opportunity for students to establish their interests in biomedical research by being involved in experimental design, critical scientific thinking, problem solving, and scientific writing and presentation.