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Journal of Virology, May 2006, p. 4890-4900, Vol. 80, No. 10
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.10.4890-4900.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Cottontail Rabbit Papillomavirus E8 Protein Is Essential for Wart Formation and Provides New Insights into Viral Pathogenesis

Mathieu Nonnenmacher,1 Jérôme Salmon,1,{dagger} Yves Jacob,1,2 Gérard Orth,1* and Françoise Breitburd1,2

Unité des Papillomavirus,1 Unité Génétique Papillomavirus et Cancer Humain, Institut Pasteur, 75724 Paris Cedex 15, France2

Received 11 December 2005/ Accepted 27 February 2006

The cottontail rabbit papillomavirus (CRPV) a and b subtypes display a conserved E8 open reading frame encoding a 50-amino-acid hydrophobic protein, with structural similarities to the E5 transmembrane oncoprotein of genital human PVs (HPVs). CRPV E8 has been reported to play a role in papilloma growth but not to be essential in papilloma formation. Here we report that the knockout of E8 start codon almost prevented wart induction upon biobalistic inoculation of viral DNA onto rabbit skin. The scarce warts induced showed very slow growth, despite sustained expression of E6 and E7 oncogenes. This points to an essential role of E8 in disturbing epidermal homeostasis. Using a yeast two-hybrid screen, we found that E8 interacted with the zinc transporter ZnT1, protocadherin 1 (PCDH1), and AHNAK/desmoyokin, three proteins as yet unrelated to viral pathogenesis or cell transformation. HPV16 E5 also interacted with these proteins in two-hybrid assay. CRPV E8 mainly localized to the Golgi apparatus and the early endosomes of transfected keratinocytes and colocalized with ZnT1, PCDH1, and AHNAK. We showed that ZnT1 and PCDH1 formed a complex and that E8 disrupted this complex. CRPV E8, like HPV16 E5, increased epidermal growth factor (EGF)-dependent extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation and both the EGF-dependent and the EGF-independent activity of activating protein-1 (AP-1). Competition experiments with a nonfunctional truncated ZnT1 protein showed that E8-ZnT1 interaction was required for AP-1 activation. Our data identify CRPV E8 as a key player in papilloma induction and unravel novel cellular targets for inducing the proliferation of keratinocytes.

* Corresponding author. Mailing address: Département de Virologie, Institut Pasteur, 25 Rue du Dr Roux, F-75724 Paris, Cedex 15, France. Phone: 33 1 40 61 30 06. Fax: 33 1 45 68 89 66. E-mail: gorth{at}pasteur.fr.

{dagger} Present address: The Johns Hopkins University School of Medicine, Department of Pharmacology and Molecular Sciences, 725 North Wolfe Street, Baltimore, MD 21205.

Journal of Virology, May 2006, p. 4890-4900, Vol. 80, No. 10
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.10.4890-4900.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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