Nicolaides, L.; (2011) Interactions of the Human Papillomavirus E6 protein and their role in the persistence of viral episomes. Doctoral thesis , UCL (University College London).

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Abstract

The E6 protein from high-risk Human Papillomaviruses (HPVs) has previously been shown to be necessary for the persistence of viral episomes in cells, however, the mechanism for this remains unclear. High-risk E6 proteins have many activities including the ability to degrade p53 and the ability to bind to and degrade PDZ proteins. In this study I aimed to further elucidate the role of E6 in the persistence of viral episomes. I used two HPV16 mutant genomes with mutations in the E6 open-reading frame; one that is unable to degrade p53 (16E6p53m), and one that lacks the PDZ-binding motif (16E6PDZ). I found that both are unable to persist episomally in cells thereby implicating these two activities of E6 in HPV episomal persistence. Upon closer investigation of the two mutant genomes, I found that the 16E6p53m genome does not replicate as efficiently as the wild-type genome. This result suggests a function for p53-degradation in genome replication, and consequently in genome persistence. Furthermore, by carrying out a more detailed analysis of the relationship between E6 and the PDZ protein hScrib, I showed that the wild-type E6 protein is stabilised by virtue of the PDZ-binding motif, present on its C-terminus. On the other hand, the mutant E6 protein that lacks the PDZ-binding motif (E6PDZ) is more susceptible to proteasomal degradation. These findings provide evidence for a previously unknown outcome of the E6-PDZ protein interaction, in stabilising wild-type E6 protein. In addition to the implications of this stabilisation in the persistence of viral episomes, it is also significant when considering the activities and properties of E6 that contribute to the development of neoplasia. Finally, I have also found that wild-type HPV16 genomes cannot persist in cells that constitutively express E6 protein, suggesting that the correct regulation of E6 expression is crucial.

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