Papillomavirus E6 cellular targets

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Alpha genus human papillomaviruses (HPV’s) cause benign squamous papillomas in which the virus persists and replicates. “Low risk” HPV types cause papillomas that while persisting, very rarely progress to malignancy, but can cause serious, even life-threatening medical complications due to the size and location of the papilloma. In both high-risk and low-risk HPV types, papilloma formation is driven by the expression of viral oncoproteins termed E6 and E7. Both high risk and low risk HPV E6 proteins associate with a cellular ubiquitin ligase termed E6AP. When high-risk E6 binds E6AP, E6 then recruits the cellular tumor suppressor p53 which is then ubiquitinated and degraded. Low-risk E6 proteins, while also binding E6AP, do not interact with p53, and the cellular targets it binds and degrades have until recently remained undescribed. Since low- risk and high-risk HPV both co-evolved on the same host, it is reasonable to speculate that there might be common cellular targets for both high and low risk E6 oncoproteins. Identifying cellular proteins that are broadly E6-targeted is a long-sought goal of the viral oncogenesis field. This application describes the first cellular target of the E6 + E6AP complex that is targeted for degradation by both high risk and low risk E6 proteins, NHERF1. Importantly, E6 proteins from cutaneous HPV’s as well as evolutionarily distant animal papillomaviruses also target the degradation of NHERF1. The broad tissue-type and broad species targeting of NHERF1 by their cognate E6 proteins argues for its importance in the papillomavirus life-cycle. We will present data showing how the targeting of NHERF1 by both high and low risk E6 augments cellular WNT signaling, and augments cell-cell competition in cells that express E6. We propose additional studies on both the mechanism of E6 interaction with NHERF1 and the consequences of NHERF1 degradation by E6.