HPV E6 and E7 oncoproteins cooperatively alter the expression of Disc Large 1 polarity protein in epithelial cells

LEIVA S.; GARDIOL D.; MARZIALI F.; CAVATORTA A. L.; DIZANZO M. P.; BRUNET AVALOS C.

Trieste

Congreso; ICGEB DNA Tumour Virus Meeting; 2019

ICGEB

Persistent infection with high-risk Human Papillomavirus (HPVs) is associated with the development of cervical cancer. The transforming activity of these viruses relies on the cooperative action of the E6 and E7 viral oncoproteins. Among the oncogenic activities of E6, the interaction and interference with cell polarity PDZ proteins have been well established. One of the most characterized PDZ targets of HPV E6 is human disc large (DLG1), a scaffolding protein involved in the control of cell polarity and proliferation. Interestingly, in cervical squamous intraepithelial lesions, alterations were observed in DLG1 expression in association to tumour progression. Moreover, the expression of both HPV E6 and E7 proteins may be responsible for the changes in DLG1 abundance and cell localization observed in the HPV-associated lesions.Due to the relevance of DLG1 deregulation in tumours, we have performed an in-depth investigation of the expression of DLG1 in the presence of the HPV oncoproteins in epithelial cells. We demonstrated that the relative abundance of HPV-18 E6 and DLG1 is a key factor that contributes to defining the expression levels and cellular localization of both proteins in a PDZ-dependent manner. We also showed that the co-expression of HPV-18 E6 and E7 produces a more striking effect on DLG1 subcellular localization and a co-distribution in the cytoplasmic region. Moreover, HPV-18 E7 is able to increase DLG1 levels, likely rescuing it from the proteasome E6-mediated degradation. These data constitutes a step forward in understanding the differential expression of DLG1 during tumour progression in an HPV-associated model.