Human papillomaviruses activate caspases upon epithelial differentiation to induce viral genome amplification

doi:10.1073/pnas.0707947104

Human papillomaviruses activate caspases upon epithelial differentiation to induce viral genome amplification

*Department of Microbiology–Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611; and
^†Laboratory of Molecular Virology, Institut de Recherches Cliniques de Montréal, 110 Pine Avenue West, Montreal, Canada H2W 1R7

Edited by Peter M. Howley, Harvard Medical School, Boston, MA, and approved October 15, 2007 (received for review August 22, 2007)

Abstract

The life cycle of human papillomaviruses (HPVs) is linked to epithelial differentiation, with late viral events restricted to the uppermost stratified layers. Our studies indicated that HPV activates capases-3, -7, and -9 upon differentiation, whereas minimal activation was observed in differentiating normal keratinocytes. Activation occurred in the absence of significant levels of apoptosis, suggesting a potential role for caspases in the viral life cycle. In support of this, the addition of caspase inhibitors significantly impaired differentiation-dependent viral genome amplification. A conserved caspase cleavage motif was identified in the replication protein E1 (⁴⁶DxxD⁴⁹) that was targeted in vitro by both recombinant caspase-3 and caspase-7. Mutation of this site inhibited amplification of viral genomes, indicating that caspase cleavage is necessary for the productive viral life cycle. Our study demonstrates that HPV activates caspases upon differentiation to facilitate productive viral replication and represents a way by which HPV controls viral gene function in differentiating cells.

Footnotes

^‡To whom correspondence should be addressed at:
Northwestern University, Department of Microbiology–Immunology, Morton Building 6-693, 303 East Chicago Avenue, Chicago, IL 60611.
E-mail: l-laimins{at}northwestern.edu
Author contributions: C.A.M. and L.A.L. designed research; C.A.M. performed research; A.F.-T. and J.A. contributed new reagents/analytic tools; C.A.M., J.A., and L.A.L. analyzed data; and C.A.M. and L.A.L. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0707947104/DC1.