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Journal of Virology, February 2003, p. 2330-2337, Vol. 77, No. 4
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.4.2330-2337.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Nuclear Entry of High-Risk Human Papillomavirus Type 16 E6 Oncoprotein Occurs via Several Pathways

Lucia G. Le Roux and Junona Moroianu*

Biology Department, Boston College, Chestnut Hill, Massachusetts 02467

Received 24 July 2002/ Accepted 20 November 2002

The E6 oncoprotein of high-risk human papillomavirus type 16 (HPV16) interacts with several nuclear transcription factors and coactivators in addition to cytoplasmic proteins, suggesting that nuclear import of HPV16 E6 plays a role in the cellular transformation process. In this study we have investigated the nuclear import pathways of HPV16 E6 in digitonin-permeabilized HeLa cells. We found that HPV16 E6 interacted with the karyopherin (Kap) {alpha}2 adapter and could enter the nucleus via a classical Kap {alpha}2ß1-mediated pathway. Interestingly, HPV16 E6 also interacted, via its basic nuclear localization signal (NLS) located at the C terminus, with both Kap ß1 and Kap ß2 import receptors. Binding of RanGTP to these Kap ßs inhibited their interaction with HPV16 E6 NLS. In agreement with these binding data, nuclear import of the HPV16 E6 oncoprotein in digitonin-permeabilized HeLa cells could be mediated by either Kap ß1 or Kap ß2. Nuclear import via these pathways required RanGDP and was independent of GTP hydrolysis by Ran. Significantly, an E6R124G mutant had reduced nuclear import activity, and the E6 deletion mutant lacking 121KKQR124 was not imported into the nucleus. The data reveal that the HPV16 E6 oncoprotein interacts via its C-terminal NLS with several karyopherins and exploits these interactions to enter the nucleus of host cells via multiple pathways.

* Corresponding author. Mailing address: Biology Department, Boston College, 140 Commonwealth Ave., Chestnut Hill, MA 02467-3811. Phone: (617) 552-1713. Fax: (617) 552-2011. E-mail: moroianu{at}bc.edu.

Journal of Virology, February 2003, p. 2330-2337, Vol. 77, No. 4
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.4.2330-2337.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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