Human scribble (Vartul) is targeted for ubiquitin-mediated degradation by the high-risk papillomavirus E6 proteins and the E6AP ubiquitin-protein ligase

The high-risk human papillomavirus (HPV) E6 proteins stimulate the ubiquiti nation and degradation of p53, dependent on the E6AP ubiquitin-protein liga se, Other proteins have also been shown to be targeted for degradation by E 6, including hDlg, the human homolog of the Drosophila melanogaster Discs l arge (Dlg) tumor suppressor. We show here that the human homolog of the Dro sophila Scribble (Vartul) (hScrib) tumor suppressor protein is also targete d for ubiquitination by the E6-E6AP complex in vitro and that expression of E6 induces degradation of hgcrib in vivo. Characterization of the E6AP-E6- hScrib complex indicated that hgcrib binds directly to E6 and that the bind ing is mediated by the PDZ domains of hScrib and a carboxyl-terminal epitop e conserved among the high-risk HPV E6 proteins. Green fluorescent protein- hScrib was localized to the periphery of MDCK cells, where it colocalized w ith ZO-1, a component of tight junctions. E6 expression resulted in lass of integrity of tight junctions, as measured by ZO-1 localization, and this e ffect was dependent on the PDZ binding epitope of E6, Thus, the high-risk H PV E6 proteins induce the degradation of the human homologs of two Drosophi la PDZ domain-containing tumor suppressor proteins, hDlg and hScrib, both o f which are associated with cell junction complexes. The fact that Scrib/Va rt and Dig appear to cooperate in a pathway that controls Drosophila epithe lial cell growth suggests that the combined targeting of hScrib and hDIg is an important component of the biologic activity of high-risk HPV E6 protei ns.