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HPV E6 targeted degradation of the discs large protein: evidence for the involvement of a novel ubiquitin ligase

Oncogene volume 19, pages 719–725 (2000)Cite this article

Abstract

The Discs Large (DLG) tumour suppressor protein is targeted for ubiquitin mediated degradation by the high risk human papillomavirus (HPV) E6 proteins. In this study we have used a mutational analysis of E6 in order to investigate the mechanism by which this occurs. We first show that the differences in the affinities of HPV-16 and of HPV-18 E6 proteins for binding DLG is reflected in their respective abilities to target DLG for degradation. A mutational analysis of HPV-18 E6 has enabled us to define regions within the carboxy terminal half of the protein which are essential for the ability of E6 to direct the degradation of DLG. Mutants within the amino terminal portion of E6 which have lost the ability to bind the E6-AP ubiquitin ligase, as measured by their ability to degrade p53, nonetheless retain the ability to degrade DLG. Significant levels of DLG degradation are also obtained using wheat germ extracts which lack E6-AP. Finally, we show that the transfer of the DLG binding domain onto the low risk HPV-6 E6 confers DLG binding activity to that protein and, most significantly, allows HPV-6 E6 to target DLG for degradation. These results indicate that E6 mediated degradation of DLG does not involve the E6-AP ubiquitin ligase and, in addition, shows that the high and low risk HPV E6 proteins most likely share a common cellular intermediary in the ubiquitin pathway.

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Acknowledgements

We are most grateful to Christian Kühne for comments on the manuscript. This work was supported in part by a research grant from the Associazione Italiana per la Ricerca sul Cancro to L Banks and grants from the National Institutes of Health (ROI CA58541), American Cancer Society (RPG-97-668-01-VM) and US Army (DAMD17-97-1-7082) to R Javier.

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Authors and Affiliations

  1. International Centre for Genetic Engineering and Biotechnology, Padriciano 99, Trieste, I-34012, Italy

    David Pim, Miranda Thomas & Lawrence Banks

  2. Division of Molecular Virology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, Texas, USA

    Ron Javier

  3. Departamento de Microbiologia, Instituto de Biologia Molecular y Celular de Rosario, Facultad de Ciencias Bioquimicas, Suipacha 531, Rosario, 2000, Argentina

    Daniela Gardiol

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  1. David Pim
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Pim, D., Thomas, M., Javier, R. et al. HPV E6 targeted degradation of the discs large protein: evidence for the involvement of a novel ubiquitin ligase. Oncogene 19, 719–725 (2000). https://doi.org/10.1038/sj.onc.1203374

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