The Role of Post Translational Modification in Regulating Human Papillomavirus (HPV) E6 Functions

Thatte, Jayashree (2018). The Role of Post Translational Modification in Regulating Human Papillomavirus (HPV) E6 Functions. PhD thesis The Open University.



The Human Papillomavirus (HPV) E6 oncoprotein from cancer-causing HPV types is highly multi-functional, capable of targeting many different cellular partners and pathways. Integral to this multi-functionality is its regulation by phosphorylation. Here I describe studies to firstly investigate when E6 is phosphorylated within the PDZ binding motif (PBM), and demonstrate a complex pattern of phosphorylation events which take place upon the exposure of the cells to different forms of stress. Most important of which is phosphorylation by kinases belonging to the core of the DNA Damage Response (DDR) machinery. Functionally this redirects E6 from interaction with PDZ substrates to association with 14-3-3 proteins. This in turn appears to contribute towards the ability of E6 to inhibit p53 transcriptional activity on a subset of p53 responsive promoters, thereby linking DDR signaling to the function of the E6 PBM. Functionally I have also been able to precisely dissect the sequence constraints within the E6 PBM governing phosphorylation by different kinases, PDZ recognition and interaction with different 14-3-3 isoforms. I also show that phospho-regulation of the E6AP ubiquitin ligase can also play a role in these pathways, and can be utilized and redirected by different HPV E6 oncoproteins with varying degrees of efficiency. Depending upon the specific HPV E6 protein, I also show the first evidence for phosphorylation at a site outside of the PBM and provide insights into the potential functional consequences thereof. Taken together, these studies shed new light on the role of E6 phosphorylation in a range of different biological activities, and begin to explain the multi-functional nature of the high risk HPV E6 proteins.

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