Journal article
AMP-Activated Protein Kinase Is Required for the Macropinocytic Internalization of Ebolavirus
Journal of virology, Vol.87(2), pp.746-755
01/2013
DOI: 10.1128/JVI.01634-12
PMCID: PMC3554099
PMID: 23115293
Abstract
Identification of host factors that are needed for Zaire Ebolavirus (EBOV) entry provides insights into the mechanism(s) of filovirus uptake, and these factors may serve as potential antiviral targets. In order to identify novel host genes and pathways involved in EBOV entry, gene array findings in the National Cancer Institute's NCI-60 panel of human tumor cell lines were correlated with permissivity for EBOV glycoprotein (GP)-mediated entry. We found that the gene encoding the γ2 subunit of AMP-activated protein kinase (AMPK) strongly correlated with EBOV transduction in the tumor panel. The AMPK inhibitor compound C inhibited infectious EBOV replication in Vero cells and diminished EBOV GP-dependent, but not Lassa fever virus GPC-dependent, entry into a variety of cell lines in a dose-dependent manner. Compound C also prevented EBOV GP-mediated infection of primary human macrophages, a major target of filoviral replication
in vivo
. Consistent with a role for AMPK in filovirus entry, time-of-addition studies demonstrated that compound C abrogated infection when it was added at early time points but became progressively less effective when added later. Compound C prevented EBOV pseudovirion internalization at 37°C as cell-bound particles remained susceptible to trypsin digestion in the presence of the inhibitor but not in its absence. Mouse embryonic fibroblasts lacking the AMPKα1 and AMPKα2 catalytic subunits were significantly less permissive to EBOV GP-mediated infection than their wild-type counterparts, likely due to decreased macropinocytic uptake. In total, these findings implicate AMPK in macropinocytic events needed for EBOV GP-dependent entry and identify a novel cellular target for new filoviral antivirals.
Details
- Title: Subtitle
- AMP-Activated Protein Kinase Is Required for the Macropinocytic Internalization of Ebolavirus
- Creators
- Andrew S Kondratowicz - Department of Microbiology, University of Iowa, Iowa City, Iowa, USACatherine L Hunt - Department of Microbiology, University of Iowa, Iowa City, Iowa, USARobert A Davey - Texas Biomedical Research Institute, San Antonio, Texas, USASara Cherry - Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, USAWendy J Maury - Department of Microbiology, University of Iowa, Iowa City, Iowa, USA
- Resource Type
- Journal article
- Publication Details
- Journal of virology, Vol.87(2), pp.746-755
- Publisher
- American Society for Microbiology
- DOI
- 10.1128/JVI.01634-12
- PMID
- 23115293
- PMCID
- PMC3554099
- ISSN
- 0022-538X
- eISSN
- 1098-5514
- Language
- English
- Date published
- 01/2013
- Academic Unit
- Microbiology and Immunology
- Record Identifier
- 9984083281802771
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