MicroRNA-548 down-regulates host antiviral response via direct targeting of IFN-λ1

Abstract

Interferon (IFN)-mediated pathways are a crucial part of the cellular response against viral infection. Type III IFNs, which include IFN-λ1, 2 and 3, mediate antiviral responses similar to Type I IFNs via a distinct receptor complex. IFN-λ1 is more effective than the other two members. Transcription of IFN-λ1 requires activation of IRF3/7 and nuclear factor-kappa B (NF-κB), similar to the transcriptional mechanism of Type I IFNs. Using reporter assays, we discovered that viral infection induced both IFN-λ1 promoter activity and that of the 3'-untranslated region (UTR), indicating that IFN-λ1 expression is also regulated at the post-transcriptional level. After analysis with microRNA (miRNA) prediction programs and 3'UTR targeting site assays, the miRNA-548 family, including miR-548b-5p, miR-548c-5p, miR-548i, miR-548j, and miR-548n, was identified to target the 3'UTR of IFN-λ1. Further study demonstrated that miRNA-548 mimics down-regulated the expression of IFN-λ1. In contrast, their inhibitors, the complementary RNAs, enhanced the expression of IFN-λ1 and IFN-stimulated genes. Furthermore, miRNA-548 mimics promoted infection by enterovirus-71 (EV71) and vesicular stomatitis virus (VSV), whereas their inhibitors significantly suppressed the replication of EV71 and VSV. Endogenous miRNA-548 levels were suppressed during viral infection. In conclusion, our results suggest that miRNA-548 regulates host antiviral response via direct targeting of IFN-λ1, which may offer a potential candidate for antiviral therapy.

Circulating microRNAs associated with prolonged overall survival in lung cancer patients treated with nivolumab

“…Interestingly, a previous study has shown that the miR-548 family (including miR-548j) is involved in regulation of interferon-k1 (IFN-k1/IL-29), an essential molecule for host response against viral infection [32]. More recently, inhibition of miR-93-3p by circular RNA has been associated with development of hepatocellular carcinoma [33].…”

Differential Expression of HPV16 L2 Gene in Cervical Cancers Harboring Episomal HPV16 Genomes: Influence of Synonymous and Non-Coding Region Variations

“…We therefore speculate that in such cases, where L2 protein potentially plays an oncogenic role, overexpression of miRNA-548 family could play a complementary role in supporting the oncogenicity of the episomal E variant isolates. This is based on a recent in vitro study demonstrating that miRNA-548 down-regulates host antiviral response via direct targeting of IFN-λ1 [49].…”

Interferon Receptor Signaling in Malignancy: A Network of Cellular Pathways Defining Biological Outcomes

“…miR-203, an IFN-inducible miR, targets IFIT1, effectively providing an inhibitory feedback loop following IFN gene activation (128). miR-548 targets the 3’ untranslated region of IFNλ1, affecting IFNλ1 expression and the expression of a number of ISGs, including the human MxA protein and 2’5’-oligoadenylate synthetase-1 (OAS1) (129). SOCS1 targeting by miR-122 in liver Huh7 cells significantly increases type I IFN expression (109).…”