Host cell reprogramming by human papillomavirus E7 proteins

/ABSTRACT Human papillomavirus (HPV)-encoded proteins engage cellular proteins to potently reprogram host cell signaling pathways, in doing so establishing a cellular environment conducive to viral replication and persistence. The HPV E6 and E7 proteins provide much of the viral reprogramming activity and, in the case of ‘high-risk’ HPV E6 and E7, so significantly disrupt cell signaling that they promote cellular transformation. Intensive research efforts have identified many host cell binding partners of HPV E7, some that interact with HPV E7 proteins from most virus genotypes and others that interact with only a subset of the HPV E7s. However, there is a major open question regarding how many of the host cell targets of high-risk and low-risk HPV E7 proteins are required to reprogram host cell signaling and, for high-risk HPV E7, to drive cellular transformation. We propose that the RB1 and PTPN14 tumor suppressors are two essential E7 targets and their inactivation dominates the biological activity of E7. RB1 is a well-known target of many HPV E7 proteins that must be inactivated for high-risk HPV to cause cellular transformation. High-risk HPV E7 proteins can degrade RB1, which is not a property of low-risk HPV E7s. It is not known how RB1 degradation, in addition to binding, enables high-risk HPV E7 to alter cell signaling or to promote cellular transformation. Moreover, RB1 inactivation is necessary but insufficient for the transforming activity of high-risk HPV E7. We discovered that a second target of many HPV E7 proteins is PTPN14. Our published and preliminary data show that HPV E7 proteins degrade PTPN14 and that PTPN14 degradation activates YAP1 signaling. We also found that high-risk HPV E7 must degrade PTPN14 and activate YAP1 to immortalize primary human keratinocytes. Our hypothesis is that RB1 degradation and PTPN14 degradation are independent activities of high-risk HPV E7 proteins that cooperate to reprogram the host cell and drive cell transformation. The aims are 1) to determine how degradation of RB1 and PTPN14 contribute to host cell reprogramming and 2) to determine how degradation of PTPN14 and RB1 contribute to HPV E7 transforming activity. Our research will determine how HPV E7 reprograms host cell signaling and how inhibiting essential activities of HPV E7 could limit cell growth. By testing whether a subset of the many proposed targets of HPV E7 underlie most of its biological activity, we will advance the understanding of viral oncoprotein activity, updating the model to reflect the established concept that altering a small number of host targets is sufficient for cellular transformation. Project Number: 1R01AI187203-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Elizabeth White (+1 co-PI) | Institution: TUFTS UNIVERSITY BOSTON, BOSTON, MA | Award Amount: $2,938,414 | Activity Code: R01 | Study Section: Molecular and Cellular Biology of Virus Infection Study Section[MCV] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01AI18720301A1