Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 18, Pages 7452-7457Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1302164110
Keywords
cervical cancer; tumor virus; RNA interference; intracellular trafficking
Categories
Funding
- National Institutes of Health (NIH) Predoctoral Training Grant [T32 AI07019]
- Leslie Warner Postdoctoral Fellowship from the Yale Cancer Center
- Ruth L. Kirschstein National Research Service Award [F32 NS070687]
- National Cancer Institute Grant [P01 CA016038]
- pilot grant from the Yale Center for Molecular Discovery
- NIH [R01 CA071878, P01 NS065719]
- Johnson & Johnson Translational Innovation Partnership Award
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Despite major advances in our understanding of many aspects of human papillomavirus (HPV) biology, HPV entry is poorly understood. To identify cellular genes required for HPV entry, we conducted a genome-wide screen for siRNAs that inhibited infection of HeLa cells by HPV16 pseudovirus. Many retrograde transport factors were required for efficient infection, including multiple subunits of the retromer, which initiates retrograde transport from the endosome to the trans-Golgi network (TGN). The retromer has not been previously implicated in virus entry. Furthermore, HPV16 capsid proteins arrive in the TGN/Golgi in a retromer-dependent fashion during entry, and incoming HPV proteins form a stable complex with retromer subunits. We propose that HPV16 directly engages the retromer at the early or late endosome and traffics to the TGN/Golgi via the retrograde pathway during cell entry. These results provide important insights into HPV entry, identify numerous potential antiviral targets, and suggest that the role of the retromer in infection by other viruses should be assessed.
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