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

Protein Cell. 2013 Feb;4(2):130-41. doi: 10.1007/s13238-012-2081-y. Epub 2012 Nov 12.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Adult
  • Antiviral Agents / pharmacology*
  • Antiviral Agents / therapeutic use
  • Base Sequence
  • Down-Regulation / drug effects*
  • Female
  • Hep G2 Cells
  • Hepatitis B, Chronic / drug therapy
  • Hepatitis B, Chronic / metabolism
  • Hepatitis B, Chronic / pathology
  • Humans
  • Interferon Regulatory Factor-3 / metabolism
  • Interferon Regulatory Factor-7 / metabolism
  • Interferons
  • Interleukins / antagonists & inhibitors
  • Interleukins / genetics
  • Interleukins / metabolism*
  • Leukocytes, Mononuclear / metabolism
  • Male
  • MicroRNAs / metabolism*
  • Middle Aged
  • NF-kappa B / metabolism
  • Poly I-C / pharmacology
  • Poly I-C / therapeutic use
  • Promoter Regions, Genetic
  • RNA Interference
  • RNA, Small Interfering / metabolism

Substances

  • 3' Untranslated Regions
  • Antiviral Agents
  • IFNL1 protein, human
  • IRF3 protein, human
  • IRF7 protein, human
  • Interferon Regulatory Factor-3
  • Interferon Regulatory Factor-7
  • Interleukins
  • MIRN548 microRNA, human
  • MicroRNAs
  • NF-kappa B
  • RNA, Small Interfering
  • Interferons
  • Poly I-C