Dissection of the Interplay Between HPV E6 and Its Cellular and Viral Targets

Sterlinko Grm, Helena (2005). Dissection of the Interplay Between HPV E6 and Its Cellular and Viral Targets. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000e958

Abstract

Whilst numerous studies have assigned different activities to the Human Papillomavirus (HPV) proteins, most of these analyses have been performed using only individual viral proteins, in the absence of other viral gene products that would be encountered in the context of a normal viral infection. Because of this, we initiated a series of studies to investigate the biological consequences of coexpressing various combinations of the HPV-encoded proteins. We show that HPV E2 and E6 exert dramatic regulatory effects upon each other's activities, which are mediated by a direct protein-protein interaction. These include relocalisation and alteration of substrate specificity, as well as the fine tuning of viral DNA replication and gene expression. At the same time L2 was found to induce enhanced accumulation of E6 in promyeloitic leukemia oncogenic domains (PODs); one consequence of which is the targeting of the POD-associated protein Daxx for proteasome mediated degradation. These findings provide unique insights into the complexity of the viral life cycle, and suggest alternative models for the role of loss of E2 and potentially of L2 during malignant progression.

Using peptides isolated from an E6-specific library the significance of the E6/E6-AP interaction for E6 target degradation was also investigated. These studies reveal striking differences in the mechanism by which E6 targets its cellular substrates for degradation and provide compelling evidence for the role of E6-associated ubiquitin ligases other than E6-AP in the degradation of certain E6 targets. This has profound importance for studies aimed at developing therapeutics to target the E6/E6-AP interaction.