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Title: Inhibition of protein kinase C promotes dengue virus replication
Authors: Warobon Noppakunmongkolchai
Teera Poyomtip
Thichakorn Jittawuttipoka
Natthanej Luplertlop
Anavaj Sakuntabhai
Sarin Chimnaronk
Siwanon Jirawatnotai
Rutaiwan Tohtong
Mahidol University. Faculty of Science. Systems Biology of Diseases Research Unit
Keywords: Open Access article;Dengue virus (DENV);Protein kinase C (PKC);Phosphorylation;Non-structural protein 5 (NS5);Viral replication;Flavivirus
Issue Date: 2016
Citation: Virology Journal. Vol. 13, (2016), 35
Abstract: Background: Dengue virus (DENV) is a member of the Flaviviridae family, transmitted to human via mosquito. DENV infection is common in tropical areas and occasionally causes life-threatening symptoms. DENV contains a relatively short positive-stranded RNA genome, which encodes ten viral proteins. Thus, the viral life cycle is necessarily rely on or regulated by host factors. Methods: In silico analyses in conjunction with in vitro kinase assay were used to study kinases that potentially phosphorylate DENV NS5. Potential kinase was inhibited or activated by a specific inhibitor (or siRNA), or an activator. Results of the inhibition and activation on viral entry/replication and host cell survival were examined. Results: Our in silico analyses indicated that the non-structural protein 5 (NS5), especially the RNA-dependent RNA polymerase (RdRp) domain, contains conserved phosphorylation sites for protein kinase C (PKC). Phosphorylation of NS5 RdRp was further verified by PKC in vitro kinase assay. Inhibitions of PKC by a PKC-specific chemical inhibitor or siRNA suppressed NS5 phosphorylation in vivo, increased viral replication and reduced viability of the DENV-infected cells. In contrary, activation of PKC effectively suppressed intracellular viral number. Conclusions: These results indicated that PKC may act as a restricting mechanism that modulates the DENV replication and represses the viral outburst in the host cells.
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