Inducible MiR-590-5p Inhibits Host Antiviral Response By Targeting The Soluble Interleukin-6(IL-6)Receptor

Viral infection triggers a series of downstream events mediated by host cells,including the activated interferon(IFN)signaling pathway and inflammatory regulatory network,which play a major role in host antiviral response.Celluar microRNAs(miRNAs)are key regulators of gene expression,which mediate gene silencing via the action of sequence-specific binding to the 3' untranslated regions(3'UTR)of target genes.Hence,miRNAs have been found to participate in a multitude of biological processes,including viral replication.miR-590-5p has been identified as an important regulator of some signaling pathways such as cell proliferation and tumorigenesis.However,little is known about its role during viral infection.In this study,we confirmed the correlation of miR-590-5p with viral infection,and revealed a positive role and the underlying mechanism of virus-induced miR-590-5p in regulating the replication of various viruses.miR-590-5p was significantly induced by DNA and RNA viruses including HSV-1,SeV,VSV,IAV,EV71 and ZIKV.Further study indicated that miR-590-5p effectively potentiated virus replication in different viral infection systems,suggesting its possibility in regulating host antivral response.As expected,miR-590-5p substantially attenuated the virus-induced expression of type I and type III IFNs and inflammatory cytokines,resulting in impaired downstream antiviral signaling.Interleukin-6 receptor(IL-6R)was identified as a target of miR-590-5p,since miR-590-5p specifically binds to IL-6R 3'UTR through base pairing.Interestingly,the role of miR-590-5p in virus-triggered signaling was abolished in IL-6R knockout cells,and this could be rescued by restoring the expression of the soluble IL-6R(sIL-6R)but not the membrane-bound IL-6R(mIL-6R),suggesting that sIL-6R is indispensable for miR-590-5p in modulating the host antiviral response.Furthermore,overexpression of miR-590-5p in A549 cells exerted an inhibitory effect on the protein levels of sIL-6R and mIL-6R,but the mRNA levels of both two receptors were not affected,indicating that miR-590-5p down-regulated endogenous sIL-6R and mIL-6R expression through a translational repression mechanism.These findings thus uncover a previously uncharacterized role of miR-590-5p in the innate immune response to viral infection,which mainly depends on sIL-6R.What's more,miR-590-5p may bear considerable potential as a new target for the development of therapies against viral infection and infection-related diseases.