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Emodin inhibits coxsackievirus B3 replication via multiple signalling cascades leading to suppression of translation

Authors :
Ye Qiu
Xin Ye
Fengping Wang
Hongxing Shen
Decheng Yang
Paul J. Hanson
Huifang M. Zhang
Source :
Biochemical Journal. 473:473-485
Publication Year :
2016
Publisher :
Portland Press Ltd., 2016.

Abstract

CVB3 (coxsackievirus 3) is a primary causal agent of viral myocarditis. Emodin is a natural compound isolated from certain plant roots. In the present study, we found that emodin inhibited CVB3 replication in vitro and in mice, and now we report an unrecognized mechanism by which emodin inhibits CVB3 replication through suppression of viral protein translation via multiple pathways. On one hand, emodin treatment inhibited Akt/mTOR (mammalian target of rapamycin) signalling and activated 4EBP1 (eukaryotic initiation factor 4R-binding protein 1), leading to suppression of translation initiation of ribosomal protein L32 encoded by a 5′-TOP (terminal oligopyrimidine) mRNA. On the other hand, emodin treatment differentially regulated multiple signal cascades, including Akt/mTORC1/p70S6K (p70 S6 kinase), ERK1/2 (extracellular-signal-regulated kinase 1/2)/p90RSK (p90 ribosomal S6 kinase) and Ca2+/calmodulin, leading to activation of eEF2K (eukaryotic elongation factor 2 kinase) and subsequent inactivation of eEF2 (eukaryotic elongation factor 2), resulting in inhibition of CVB3 VP1 (viral protein 1) synthesis. These data imply that eEF2K is a major factor mediating cross-talk of different arms of signalling cascades in this signal network. This notion was verified by either overexpressing eEF2K or treating the cells with siRNAs or eEF2K inhibitor A484954. We showed further that the emodin-induced decrease in p70S6K phosphorylation plays a dominant positive role in activation of eEF2K and in turn in conferring the antiviral effect of emodin. This finding was further solidified by expressing constitutively active and dominant-negative Akt. Collectively, our data reveal that emodin inhibits viral replication through impairing translational machinery and suppression of viral translation elongation.

Details

ISSN :
14708728 and 02646021
Volume :
473
Database :
OpenAIRE
Journal :
Biochemical Journal
Accession number :
edsair.doi.dedup.....55c8a28459d100ebaf39b0b3ed08d031
Full Text :
https://doi.org/10.1042/bj20150419