Mitotic control of human papillomavirus genome-containing cells is regulated by the function of the PDZ-binding motif of the E6 oncoprotein.
The function of a conserved PDS95/DLG1/ZO1 (PDZ) binding motif (E6 PBM) at the C-termini of E6 oncoproteins of high-risk human papillomavirus (HPV) types contributes to the development of HPV-associated malignancies. Here, using a primary human keratinocyte-based model of the high-risk HPV18 life cycle, we identify a novel link between the E6 PBM and mitotic stability. In cultures containing a mutant genome in which the E6 PBM was deleted there was an increase in the frequency of abnormal mitoses, including multinucleation, compared to cells harboring the wild type HPV18 genome. The loss of the E6 PBM was associated with a significant increase in the frequency of mitotic spindle defects associated with anaphase and telophase. Furthermore, cells carrying this mutant genome had increased chromosome segregation defects and they also exhibited greater levels of genomic instability, as shown by an elevated level of centromere-positive micronuclei. In wild type HPV18 genome-containing organotypic cultures, the majority of mitotic cells reside in the suprabasal layers, in keeping with the hyperplastic morphology of the structures. However, in mutant genome-containing structures a greater proportion of mitotic cells were retained in the basal layer, which were often of undefined polarity, thus correlating with their reduced thickness. We conclude that the ability of E6 to target cellular PDZ proteins plays a critical role in maintaining mitotic stability of HPV infected cells, ensuring stable episome persistence and vegetative amplification.
['Marsh|Elizabeth K|EK|', 'Delury|Craig P|CP|', 'Davies|Nicholas J|NJ|', 'Weston|Christopher J|CJ|', 'Miah|Mohammed A L|MAL|', 'Banks|Lawrence|L|', 'Parish|Joanna L|JL|', 'Higgs|Martin R|MR|', 'Roberts|Sally|S|']
D020816:Amino Acid Motifs D002478:Cells, Cultured D004268:DNA-Binding Proteins D016679:Genome, Viral D052161:Human papillomavirus 18 D006801:Humans D015603:Keratinocytes D008938:Mitosis D016297:Mutagenesis, Site-Directed D009154:Mutation D009856:Oncogene Proteins, Viral D054731:PDZ Domains D010766:Phosphorylation D011485:Protein Binding D014779:Virus Replication
human papillomavirus E6 PDZ proteins HPV life cycle mitosis