ALTERATIONS ON DISC LARGE 1 POLARITY PROTEIN EXPRESSION DURING HPV ONCOGENESIS?

DIZANZO MP, BUGNON VALDANO M, MARZIALI F, LEIVA S, CAVATORTA AL, BANKS L, GARDIOL D.

Congreso; LVI Reunión Anual de SAIB; 2020

SAIB

The tumour processes are related to the deregulation of cellular polarity proteins which are involved in cell division, morphology and proliferation. High-risk oncogenic human papillomaviruses (HPV) are associated to the development of cervical cancer. The HPV E6 viral oncoprotein is able to interact with the human Disc large polarity protein (DLG1) and promotes its proteasomal degradation. The expression of E6 and E7 HPV oncoproteins in organotypic cultures results in a redistribution of DLG1 from the cell contacts to the cytoplasm, as well as an increase in DLG1 levels. This is in agreement with previous studies using biopsies of cervical lesions where it was also observed the same changes in DLG1 expression. In order to understand the molecular mechanisms involved in this deregulation of DLG1, we performed a series of analyses in cultured cells.We studied the localization and levels of DLG1 in the presence of HPV E6 and E7. We were able to detect the relocalization of DLG1 by immunofluorescence and an increase in DLG1 abundance in the insoluble cell fraction. These results suggest that viral oncoproteins promote the stabilization of DLG1 in the cytoplasm with probable changes in its oncosuppressive functions. Even, we demonstrated that E7 is able to increase DLG1 protein levels probably by contributing to its stabilization and/or preventing its degradation in the presence of E6. A mutated version of E7 was used to elucidate the mechanisms involved in these observations. We demonstrated that the phosphorylation of the Conserved Region 2 domain of E7 by Casein Kinase II (CKII) is necessary to alter DLG1 expression in the HPV context. E7 is capable to interact with numerous cell targets and its phosphorylation may favour these interactions; therefore, it is likely that CKII phosphorylation regulates key E7 functions required for the stabilization of DLG1. These data together contribute to the molecular understanding of the alteration of cell polarity during the oncogenesis mediated by high-risk HPV.