title: 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.
authors.affiliation: The State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Yongkui
authors.initials: Y
authors.lastname: Li
authors.forename: Jiajia
authors.initials: J
authors.lastname: Xie
authors.forename: Xiupeng
authors.initials: X
authors.lastname: Xu
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Fang
authors.initials: F
authors.lastname: Ao
authors.forename: Yushun
authors.initials: Y
authors.lastname: Wan
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhu
mesh_terms: D020413:3' Untranslated Regions; D000328:Adult; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001483:Base Sequence; D015536:Down-Regulation / Q000187:drug effects*; D005260:Female; D056945:Hep G2 Cells; D019694:Hepatitis B, Chronic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D050839:Interferon Regulatory Factor-7 / Q000378:metabolism; D007372:Interferons; D007378:Interleukins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D011070:Poly I-C / Q000494:pharmacology / Q000627:therapeutic use; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D000095022:Interferon Lambda
chemical_list: D020413:3' Untranslated Regions; D000998:Antiviral Agents; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D007372:Interferons; D007378:Interleukins; D035683:MicroRNAs; D016328:NF-kappa B; D011070:Poly I-C; D034741:RNA, Small Interfering; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C494232:IRF3 protein, human; C494234:IRF7 protein, human; C561887:MIRN548 microRNA, human