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Interactome analysis of the human respiratory Syncytial Virus RNA polymerase complex identifies protein chaperones as important cofactors that promote L-Protein stability and RNA synthesis
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(2015) Interactome analysis of the human respiratory Syncytial Virus RNA polymerase complex identifies protein chaperones as important cofactors that promote L-Protein stability and RNA synthesis. Journal of Virology, Volume 89 (Number 2). pp. 917-930. doi:10.1128/JVI.01783-14 ISSN 0022-538X.
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Official URL: http://dx.doi.org/10.1128/JVI.01783-14
Abstract
The human respiratory syncytial virus (HRSV) core viral RNA polymerase comprises the large polymerase protein (L) and its cofactor, the phosphoprotein (P), which associate with the viral ribonucleoprotein complex to replicate the genome and, together with the M2-1 protein, transcribe viral mRNAs. While cellular proteins have long been proposed to be involved in the synthesis of HRSV RNA by associating with the polymerase complex, their characterization has been hindered by the difficulty of purifying the viral polymerase from mammalian cell culture. In this study, enhanced green fluorescent protein (EGFP)-tagged L- and P-protein expression was coupled with high-affinity anti-GFP antibody-based immunoprecipitation and quantitative proteomics to identify cellular proteins that interacted with either the L- or the P-proteins when expressed as part of a biologically active viral RNP. Several core groups of cellular proteins were identified that interacted with each viral protein including, in both cases, protein chaperones. Ablation of chaperone activity by using small-molecule inhibitors confirmed previously reported studies which suggested that this class of proteins acted as positive viral factors. Inhibition of HSP90 chaperone function in the current study showed that HSP90 is critical for L-protein function and stability, whether in the presence or absence of the P-protein. Inhibition studies suggested that HSP70 also disrupts virus biology and might help the polymerase remodel the nucleocapsid to allow RNA synthesis to occur efficiently. This indicated a proviral role for protein chaperones in HRSV replication and demonstrates that the function of cellular proteins can be targeted as potential therapeutics to disrupt virus replication.
Item Type: | Journal Article | ||||||||
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Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) | ||||||||
Journal or Publication Title: | Journal of Virology | ||||||||
Publisher: | American Society for Microbiology | ||||||||
ISSN: | 0022-538X | ||||||||
Official Date: | January 2015 | ||||||||
Dates: |
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Volume: | Volume 89 | ||||||||
Number: | Number 2 | ||||||||
Page Range: | pp. 917-930 | ||||||||
DOI: | 10.1128/JVI.01783-14 | ||||||||
Status: | Peer Reviewed | ||||||||
Publication Status: | Published | ||||||||
Access rights to Published version: | Restricted or Subscription Access |
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