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

Cary A. Moody, Amelie Fradet-Turcotte, Jacques Archambault, Laimonis A. Laimins*

*Corresponding author for this work

Research output: Contribution to journalArticle

78 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)19541-19546
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number49
DOIs
StatePublished - Dec 4 2007

Keywords

  • Apoptosis
  • Pathogenesis
  • Replication

ASJC Scopus subject areas

  • General

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