期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 104, 期 49, 页码 19541-19546出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0707947104
关键词
replication; pathogenesis; apoptosis
资金
- CIHR [68885-1] Funding Source: Medline
- NCI NIH HHS [R01 CA074202, R37 CA074202, R01CA CA59655, R01CA74202, R01 CA059655, R37 CA074202-12] Funding Source: Medline
- NIAMS NIH HHS [T32 AR007593, 5T32 AR007593] Funding Source: Medline
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 ((46)DxxD(49)) 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.
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