Contribution of Human Papillomavirus E6 PDZ-Binding Activity to Virus-Induced Pathogenesis

Kranjec, Christian (2013). Contribution of Human Papillomavirus E6 PDZ-Binding Activity to Virus-Induced Pathogenesis. PhD thesis The Open University.



It is clear that the targeting of PDZ-containing substrates by E6 is important for the normal viral life cycle and for the progression to malignancy. However, which of these PDZ domain-containing proteins is relevant for HPV pathology is still elusive. In this study, we provide the evidence that different PDZ domain-containing proteins are differentially targeted by E6. With these experiments, we identified MAGI-1 as a sensitive proteolytic substrate for both the HPV-16 and HPV-18 E6 oncoproteins. We show that E6 promotes the degradation of membrane-bound and nuclear pools of MAGI-1, and the silencing of E6 expression resulted in the MAGI-1-mediated junctional recruitment of ZO-1. Using a mutant MAGI-1, resistant to E6-mediated degradation, we also show that its expression in HeLa cells also promotes membrane recruitment of the tight junction-associated proteins ZO-1 and PAR3, represses cell proliferation and promotes apoptosis. These findings suggest that E6-mediated inhibition of MAGI-1 function perturbs tight junction assembly, with concomitant stimulation of proliferation and inhibition of apoptosis. We also found that the cell polarity regulator hScrib is differentially targeted by HPV-16 and HPV-18 Ed-mediated degradation. Surprisingly, we found that residual levels of hScrib expression are required for the maintenance of high levels of HPV-18 E6 expression in HeLa cells. This is not due to an effect on E6 stability or transcription, but rather is due to an effect upon E6 translation. We provide evidence that hScrib and E6 both regulate the PI3K/mTORC1 pathway, and that hScrib might regulate cap-dependent translation through the modulation of the mTORCl effector S6 kinase. This provides an unexpected role for hScrib in the regulation of tissue homeostasis, and provides further evidence that E6, by fine-tuning the levels of expression of its different cellular substrates, can impact upon a wide range of biological processes implicated in the pathogenesis of cervical cancer.

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