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Multi-faceted proteomic characterization of host protein complement of Rift Valley fever virus virions and identification of specific heat shock proteins, including HSP90, as important viral host factors
Journal article   Open access   Peer reviewed

Multi-faceted proteomic characterization of host protein complement of Rift Valley fever virus virions and identification of specific heat shock proteins, including HSP90, as important viral host factors

Jonathan E Nuss, Kylene Kehn-Hall, Ashwini Benedict, Julie Costantino, Michael Ward, Brian D Peyser, Cary J Retterer, Lyal E Tressler, Laura M Wanner, Hugh F McGovern, …
PloS one, Vol.9(5), pp.e93483-e93483
2014
DOI: 10.1371/journal.pone.0093483
PMCID: PMC4014464
PMID: 24809507
url
https://doi.org/10.1371/journal.pone.0093483View
Published (Version of record) Open Access

Abstract

Rift Valley fever is a potentially fatal disease of humans and domestic animals caused by Rift Valley fever virus (RVFV). Infection with RVFV in ruminants can cause near 100% abortion rates and recent outbreaks in naïve human populations have suggested case fatality rates of greater than thirty percent. To elucidate the roles that host proteins play during RVFV infection, proteomic analysis of RVFV virions was conducted using complementary analytical approaches, followed by functional validation studies of select identified host factors. Coupling the more traditional Gel LC/MS/MS approach (SDS PAGE followed by liquid chromatography tandem mass spectrometry) with an alternative technique that preserves protein complexes allowed the protein complement of these viral particles to be thoroughly examined. In addition to viral proteins present within the virions and virion-associated host proteins, multiple macromolecular complexes were identified. Bioinformatic analysis showed that host chaperones were among over-represented protein families associated with virions, and functional experiments using siRNA gene silencing and small molecule inhibitors identified several of these heat shock proteins, including heat shock protein 90 (HSP90), as important viral host factors. Further analysis indicated that HSP inhibition effects occur during the replication/transcription phase of the virus life cycle, leading to significant lowering of viral titers without compromising the functional capacity of released virions. Overall, these studies provide much needed further insight into interactions between RVFV and host cells, increasing our understanding of the infection process and suggesting novel strategies for anti-viral development. In particular, considering that several HSP90 inhibitors have been advancing through clinical trials for cancer treatment, these results also highlight the exciting potential of repurposing HSP90 inhibitors to treat RVF.
 Proteomics Gene Silencing Heat-Shock Proteins - genetics Heat-Shock Proteins - metabolism HSP90 Heat-Shock Proteins - genetics HSP90 Heat-Shock Proteins - metabolism Rift Valley Fever - virology Rift Valley fever virus - genetics Rift Valley fever virus - metabolism RNA, Small Interfering Tandem Mass Spectrometry Viral Proteins - genetics Viral Proteins - metabolism Virion - genetics Virion - metabolism

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