Human papillomavirus (HPV)-18 E6 oncoprotein interferes with the epithelial cell polarity Par3 protein

High-risk human papillomavirus (HPV) infection is the principal risk factor for the development of cervical cancer. The HPV E6 oncopr otein has the ability to target and inter fere with several PSD -95/DLG/ZO-1 (PDZ) domain -containing proteins that are invo lved in the control of cell polarity. This funct ion can be significant for E6 oncog enic activity because a deficiency in cell polarisation is a mark er of tumour progressio n. The establishment and control of polarity in epithelial cells depend on the correct asymmetrical distrib ution of proteins and lipids at the cell borders and on specialised cell junction s. In this repor t, we have investigated the effects of HPV E6 protein on the polarity mac hinery, with a focus on the PDZ part itioning defective 3 (Par3) protein, which is a key compone nt of tight junctions (TJ) and the polarity netwo rk. We demonstrate that E6 is able to bind and induce the mislocalisation of Par3 pro tein in a PDZ-depend ent manner without significant reduction in Par3 protein levels. In addition, the high-risk HPV-18 E6 protein promo tes a delay in TJ formation whe n analysed by calcium switch assays. Taken together, the data presented in this study contribute to our understanding of the mole cular mechani sm by which HPVs induce the loss of cell polarity, with potent ial implications for the development and progressio n of HPV-assoc iated tumours.