Zhou Bingfei, Chu Min, Xu Shanshan, Chen Xiong, Liu Yongjuan, Wang Zhihao, Zhang Fengfeng, Han Song, Yin Jun, Peng Biwen, He Xiaohua, Liu Wanhong
Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, No. 185, Donghu Road, Wuchang District, Wuhan, 430071 China ; Hubei Provincial Key Laboratory of Developmentally Originated Disease, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071 China.
Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, No. 185, Donghu Road, Wuchang District, Wuhan, 430071 China.
Cell Biosci. 2017 Jan 14;7:7. doi: 10.1186/s13578-017-0135-9. eCollection 2017.
Human 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.
In 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.
Our 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.
肠道病毒71型（EV71）可引发严重的手足口病，并伴有神经并发症。在EV71与宿主相互作用的过程中，该病毒会颠覆宿主细胞机制以实现自身复制。然而，微小RNA（miRNA）在此过程中的作用仍不清楚。
在本研究中，我们发现miRNA hsa-let-7c-5p在EV71感染的横纹肌肉瘤细胞中显著上调。hsa-let-7c-5p的过表达促进了病毒的复制，而hsa-let-7c-5p抑制剂则抑制了病毒复制。此外，hsa-let-7c-5p靶向丝裂原活化蛋白激酶激酶激酶激酶4（MAP4K4）并抑制其表达。有趣的是，MAP4K4表达的下调导致EV71复制增加。此外，MAP4K4基因敲低或用hsa-let-7c-5p模拟物转染会导致c-Jun氨基末端激酶（JNK）信号通路激活，而hsa-let-7c-5p抑制剂则抑制该通路的激活。此外，EV71感染促进JNK通路激活以促进病毒复制。
我们的数据表明，hsa-let-7c-5p通过抑制MAP4K4表达促进了EV71复制，这可能与病毒对JNK通路的颠覆有关。这些结果可能揭示了EV71抵御细胞反应的一种新机制。此外，这些发现可能有助于开发用于未来治疗的新抗病毒策略。
