The hScrib/Dlg apico-basal control complex is differentially targeted by HPV-16 and HPV-18 E6 proteins.
The E6 proteins of the high-risk Human papillomaviruses (HPV) types have a well-documented ability to target certain cellular proteins for ubiquitin-mediated degradation via the proteasome. Previous studies have shown that E6 proteins interact differently with different target proteins, and that the viral proteins, depending upon the target, may recruit diverse cellular ubiquitin-protein ligases. In this study, we have examined the abilities of E6 proteins from HPV-16 and HPV-18 to interact with and induce the degradation of two PDZ domain-containing targets, Dlg and hScrib. We have also mapped the binding site of E6 on hScrib and shown that the interaction of E6 with hScrib is distinct from its interactions with other PDZ domain-containing targets. This is reflected in the efficiency with which the two viral E6 proteins can inhibit hScrib's suppression of cell transformation.Dlg and hScrib have complementary activities in the control of epithelial cell polarity and the fact that both are targeted by high-risk HPV E6 proteins underlines their importance. Our finding that they are each targeted differently by HPV-16 and HPV-18 E 6 s suggests that the two viruses are subjected to somewhat different constraints and provides a possible explanation for the apparent redundancy in targeting both parts of this important control mechanism.
Thomas
Miranda
M
International Centre for Genetic Engineering and Biotechnology, Padriciano 99, 34012 Trieste, Italy.
Massimi
Paola
P
Navarro
Christel
C
Borg
Jean-Paul
JP
Banks
Lawrence
L
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002461:Cell Line, Transformed; D004268:DNA-Binding Proteins / Q000502:physiology*; D000074288:Discs Large Homolog 1 Protein; D004285:Dogs; D006868:Hydrolysis; D008565:Membrane Proteins / Q000502:physiology*; D008969:Molecular Sequence Data; D009856:Oncogene Proteins, Viral / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D012097:Repressor Proteins / Q000502:physiology*; D025521:Tumor Suppressor Proteins
D048868:Adaptor Proteins, Signal Transducing; C513314:DLG1 protein, human; D004268:DNA-Binding Proteins; D000074288:Discs Large Homolog 1 Protein; C501119:Dlg1 protein, rat; C068651:E6 protein, Human papillomavirus type 16; C052603:E6 protein, Human papillomavirus type 18; D008565:Membrane Proteins; D009856:Oncogene Proteins, Viral; D012097:Repressor Proteins; C480591:SCRIB protein, human; D025521:Tumor Suppressor Proteins