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Journal of Virology, November 2008, p. 10408-10417, Vol. 82, No. 21
0022-538X/08/$08.00+0     doi:10.1128/JVI.00902-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

E6 Proteins from Multiple Human Betapapillomavirus Types Degrade Bak and Protect Keratinocytes from Apoptosis after UVB Irradiation{triangledown}

Michael P. Underbrink ,1,2,{dagger},{ddagger} Heather L. Howie,1,{ddagger} Kristin M. Bedard,1 Jennifer I. Koop,1 and Denise A. Galloway1*

Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington,1 Department of Otolaryngology, University of Washington Medical Center, Seattle, Washington2

Received 30 April 2008/ Accepted 8 August 2008

Human papillomavirus (HPV) types from the beta genus (beta-HPVs) have been implicated in the development of skin cancer. A potentially important aspect of their carcinogenic role is the ability of the E6 protein to degrade the proapoptotic family member Bak, which gives cells the ability to survive UV damage. However, it is unknown if the ability to degrade Bak is limited to certain beta-HPV types or whether E6 expression in keratinocytes affects other proteins important for apoptosis signaling. We tested the abilities of E6 proteins from several representative members of the beta-HPVs to degrade Bak and protect UV-treated keratinocytes from apoptosis. The E6 proteins of the beta-HPV type 5 (HPV5), -8, -20, -22, -38, -76, -92, and -96, as well as the alpha genus HPV HPV16, all degraded Bak or prevented its accumulation following UV treatment but did not degrade Bak constitutively. In addition, when tested using HPV16 E6 (16E6) and 8E6 as representative E6 proteins from the alpha and beta genera, respectively, Bak degradation was dependent on the E3 ubiquitin ligase, E6AP. Other important regulators of apoptotic signaling were examined and found to be unperturbed by the expression of the beta-HPV E6 proteins. Importantly, the expression of beta-HPV E6 proteins protected keratinocytes from apoptosis to the same extent as 16E6-expressing cells. In conclusion, several of the beta-HPV types possess the ability to protect UV-treated keratinocytes from apoptosis by reducing levels of Bak in those cells, thus blocking the intrinsic apoptotic pathway.

* Corresponding author. Mailing address: Division of Human Biology, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, C1-015, Box 19024, Seattle, WA 98109-1024. Phone: (206) 667-4500. Fax: (206) 667-5815. E-mail: dgallowa{at}fhcrc.org

{triangledown} Published ahead of print on 20 August 2008.

{dagger} Present address: Departments of Otolaryngology—Head and Neck Surgery and Microbiology, University of Texas Medical Branch, Galveston, TX.

{ddagger} These authors contributed equally to this work.

Journal of Virology, November 2008, p. 10408-10417, Vol. 82, No. 21
0022-538X/08/$08.00+0     doi:10.1128/JVI.00902-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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