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Journal of Virology, July 2004, p. 7199-7207, Vol. 78, No. 13
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.13.7199-7207.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

E1{wedge}E4 Protein of Human Papillomavirus Type 16 Associates with Mitochondria

Kenneth Raj,1,2 Samuel Berguerand,1 Shirley Southern,2 John Doorbar,2 and Peter Beard1*

Swiss Institute for Experimental Cancer Research and NCCR Molecular Oncology, 1066 Epalinges, Switzerland ,1 National Institute of Medical Research, Mill Hill, London, England2

Received 30 September 2003/ Accepted 10 March 2004

The human papillomavirus (HPV) E1{wedge}E4 protein is the most abundantly expressed viral protein in HPV-infected epithelia. It possesses diverse activities, including the ability to bind to the cytokeratin network and to DEAD-box proteins, and in some cases induces the collapse of the former. E1{wedge}E4 is also able to prevent the progression of cells into mitosis by arresting them in the G2 phase of the cell cycle. In spite of these intriguing properties, the role of this protein in the life cycle of the virus is not clear. Here we report that after binding to and collapsing the cytokeratin network, the HPV type 16 E1{wedge}E4 protein binds to mitochondria. When cytokeratin is not present in the cell, E1{wedge}E4 appears associated with mitochondria soon after its synthesis. The leucine cluster within the N-terminal portion of the E1{wedge}E4 protein is pivotal in mediating this association. After the initial binding to mitochondria, the E1{wedge}E4 protein induces the detachment of mitochondria from microtubules, causing the organelles to form a single large cluster adjacent to the nucleus. This is followed by a severe reduction in the mitochondrial membrane potential and an induction of apoptosis. HPV DNA replication and virion production occur in terminally differentiating cells which are keratin-rich, rigid squamae that exfoliate after completion of the differentiation process. Perturbation of the cytokeratin network and the eventual induction of apoptotic properties are processes that could render these unyielding cells more fragile and ease the exit of newly synthesized HPVs for subsequent rounds of infection.

* Corresponding author. Mailing address: Swiss Institute for Experimental Cancer Research (ISREC), Chemin des Boveresses 155, CH-1066 Epalinges, Switzerland. Phone: 41 21 692 5921. Fax: 41 21 652 6933. E-mail: Peter.Beard{at}isrec.unil.ch.

Journal of Virology, July 2004, p. 7199-7207, Vol. 78, No. 13
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.13.7199-7207.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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