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J. Biol. Chem., Vol. 280, Issue 43, 36088-36098, October 28, 2005

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Nucleo-cytoplasmic Shuttling of High Risk Human Papillomavirus E2 Proteins Induces Apoptosis^*

From the Unité Expression Génétique et Maladies, CNRS FRE 2850, Institut Pasteur, 25 rue du Dr. Roux, 75724 Paris cedex 15, France

Human Papillomavirus (HPV) E2 proteins are the major viral regulators of transcription and replication during the viral life cycle. In addition to these conserved functions, we show that E2 proteins from high risk HPV types 16 and 18, which are associated with cervical cancer, can induce apoptosis. In contrast, E2 proteins from low risk HPV types 6 and 11, which are associated with benign lesions, do not cause cell death. We show that the ability to induce apoptosis is linked to the intracellular localization of the respective E2 proteins rather than to inherent properties of the proteins. Although low risk HPV E2 proteins remain strictly nuclear, high risk HPV E2 proteins are present in both the nucleus and the cytoplasm of expressing cells due to exportin-1 receptor (CRM1)-dependent nucleo-cytoplasmic shuttling. Induction of apoptosis is caused by accumulation of E2 in the cytoplasm and involves caspase 8 activation. We speculate that disruption of the E2 gene during viral genome integration in cervical carcinoma provides a means to avoid E2-induced apoptosis and allow initiation of carcinogenesis.

Received for publication, May 10, 2005 , and in revised form, August 31, 2005.

^* This work was supported by the Association pour la Recherche sur le Cancer and the Ligue Contre le Cancer comité de Paris. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by a Ministère de l'Education Nationale, de la Recherche et de la Technologie fellowship and by a fellowship from the Association pour la Recherche sur le Cancer.

² Supported by an Association pour la Recherche sur le Cancer fellowship.

³ To whom correspondence should be addressed. Tel.: 33-1-45688526; Fax: 33-1-40613033; E-mail; fthierry{at}pasteur.fr.

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