The role of HPV E1 in regulating the NRF2-KEAP1 pathway

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Persistent HPV infections alone are linked to ~ 4.5% of the total cancer incidence worldwide and can cause up to six different cancers. The global incidence of HPV-positive HNSCC is currently on the rise, particularly among younger adults. Despite these tumors responding more readily to treatment compared to HPV- HNSCC, a subset of patients (~10%) will fail therapy. The global health burden of HPV+ cancers and the growing incidence of HPV-related HNSCC underscore the need to expand our knowledge of HPV biology to inform the design of targeted therapeutics. A growing body of literature highlights the function of NRF2 in HPV-associated cancers. As NRF2 is implicated in numerous cancers, including ~30% of solid tumors, and their failure to respond to therapies, this pathway provides a potential therapeutic vulnerability that could be targeted in chronic HPV infection and HPV-associated cancers. To date, we have an incomplete understanding of how NRF2 is activated in HPV-infected cells. It was recently discovered that HPV E1 directly interacts with KEAP1 and we have validated this finding. This interaction phenocopies inactivating mutations in the CUL3-KEAP1-NRF2 pathway to activate NRF2 transcriptional activity. How E1 binds to KEAP1 to activate NRF2 and the conservation of this E1 function across different HPV types is currently unknown. In this proposal, we will determine the molecular mechanism by which HPV E1 activates NRF2. We hypothesize that E1 functions as a viral NRF2 mimetic to compete for KEAP1 binding. This hypothesis will be tested through 2 specific aims. In Aim 1, we will establish the molecular determinants for E1 engagement of KEAP1 and NRF2 activation. We will also assess the ability of both high-risk and low-risk HPV types to bind KEAP1 and activate NRF2. In Aim2, we will determine the structural and biophysical basis for E1-KEAP1 interactions. The ultimate goal and the overall impact of this project are to advance our understanding of HPV regulation of NRF2 signaling by the agonistic viral protein E1. This work will in turn enable us to study the E1-KEAP1-NRF2 axis as a novel vulnerability that could be targeted in chronic HPV infection and HPV-associated cancers, which currently lack targeted therapy.