Hsa-let-7c-5p augments enterovirus 71 replication through viral subversion of cell signaling in rhabdomyosarcoma cells

Bingfei Zhou,Jun Yin,Wanhong Liu,Song Han,Xiaohua He,Biwen Peng,Zhihao Wang,Fengfeng Zhang,Xiong Chen,Yongjuan Liu,Min Chu,Shanshan Xu

doi:10.1186/s13578-017-0135-9

Abstract

BackgroundHuman enterovirus 71 (EV71) causes severe hand, foot and mouse disease, accompanied by neurological complications. During the interaction between EV71 and the host, the virus subverts host cell machinery for its own replication. However, the roles of microRNAs (miRNAs) in this process remain obscure.ResultsIn this study, we found that the miRNA hsa-let-7c-5p was significantly upregulated in EV71-infected rhabdomyosarcoma cells. The overexpression of hsa-let-7c-5p promoted replication of the virus, and the hsa-let-7c-5p inhibitor suppressed viral replication. Furthermore, hsa-let-7c-5p targeted mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) and inhibited its expression. Interestingly, downregulation of MAP4K4 expression led to an increase in EV71 replication. In addition, MAP4K4 knockdown or transfection with the hsa-let-7c-5p mimic led to activation of the c-Jun NH2-terminal kinase (JNK) signaling pathway, whereas the hsa-let-7c-5p inhibitor inhibited activation of this pathway. Moreover, EV71 infection promoted JNK pathway activation to facilitate viral replication.ConclusionsOur data suggested that hsa-let-7c-5p facilitated EV71 replication by inhibiting MAP4K4 expression, which might be related to subversion of the JNK pathway by the virus. These results may shed light on a novel mechanism underlying the defense of EV71 against cellular responses. In addition, these findings may facilitate the development of new antiviral strategies for use in future therapies.

Highlights

Human enterovirus 71 (EV71) causes severe hand, foot and mouse disease, accompanied by neurological complications
Mature miRNA hsa‐let‐7c‐5p expression is upregulated during EV71 infection According to current and our previous studies, rhabdomyosarcoma (RD) cells and the Henrietta Lacks strain of cancer (HeLa) cells can be used as in vitro models to investigate the interplay between EV71 and its host [16, 27,28,29]
To determine whether hsa-let-7c-5p is involved in EV71 infection, we first examined the expression of mature hsa-let-7c-5p in uninfected and EV71-infected RD cells by stem-loop quantitative reverse transcription polymerase chain reaction

Summary

Introduction

Human enterovirus 71 (EV71) causes severe hand, foot and mouse disease, accompanied by neurological complications. Human enterovirus 71 (EV71), which belongs to the genus Enterovirus in the family Picornaviridae, is a type of single-stranded positive-sense RNA virus that is known to be a major cause of hand, foot and mouth disease (HFMD) in young children. This virus may cause serious neurological complications compared with other pathogens associated with HFMD [1]. Increasing evidence indicates that miRNAs play a role in the pathogenesis of viral infectious diseases Both DNA and RNA viruses can act as boosters, destroyers and hijackers in the regulation of cellular miRNAs to facilitate progression of their life cycles [15, 16]

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