Human and primate tumour viruses use PDZ binding as an evolutionarily conserved mechanism of targeting cell polarity regulators.
A unique feature of the cancer-causing mucosotropic human papillomaviruses (HPVs) is the ability of their E6 proteins to interact with a number of PDZ domain-containing cellular substrates, including the cell polarity regulators hDlg and hScrib. These interactions are essential for the ability of these viruses to induce malignant progression. Rhesus papillomaviruses (RhPV) are similar to their human counterparts in that they also cause anogenital malignancy in their host, the Rhesus Macaque. However, unlike HPV E6, the RhPV E6 has no PDZ-binding motif. We now show that such a motif is present on the RhPV E7 oncoprotein. This motif specifically confers PDZ-binding activity and directs the interaction of RhPV E7 with the cell polarity regulator Par3, which it targets for proteasome-mediated degradation. These results demonstrate an amazing evolutionary conservation of function between the RhPV and the HPV oncoproteins, where both target proteins of the same cell polarity control network, although through different components and pathways.
Tomaić
V
V
International Centre for Genetic Engineering and Biotechnology, Trieste, Italy.
Gardiol
D
D
Massimi
P
P
Ozbun
M
M
Myers
M
M
Banks
L
L
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D016764:Cell Polarity; D017124:Conserved Sequence; D000074288:Discs Large Homolog 1 Protein; D019143:Evolution, Molecular; D006801:Humans; D008253:Macaca mulatta / Q000821:virology*; D008565:Membrane Proteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D009856:Oncogene Proteins, Viral / Q000737:chemistry / Q000378:metabolism*; D009858:Oncogenic Viruses / Q000378:metabolism; D054731:PDZ Domains; D027383:Papillomaviridae / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C513314:DLG1 protein, human; D000074288:Discs Large Homolog 1 Protein; D008565:Membrane Proteins; D009856:Oncogene Proteins, Viral; C509689:PARD3 protein, human; C480591:SCRIB protein, human; D025521:Tumor Suppressor Proteins