MicroRNA-146a feedback inhibits RIG-I-dependent Type I IFN production in macrophages by targeting TRAF6, IRAK1, and IRAK2

J Immunol. 2009 Aug 1;183(3):2150-8. doi: 10.4049/jimmunol.0900707. Epub 2009 Jul 13.


Upon recognition of viral components by pattern recognition receptors, including TLRs and retinoic acid-inducible gene I (RIG-I)- like helicases, cells are activated to produce type I IFN and proinflammatory cytokines. These pathways are tightly regulated by host to prevent inappropriate cellular response, but viruses can down-regulate these pathways for their survival. Recently, identification of negative regulators for cytoplasmic RNA-mediated antiviral signaling, especially the RIG-I pathway, attract much attention. However, there is no report about negative regulation of RIG-I antiviral pathway by microRNAs (miRNA) to date. We found that vesicular stomatitis virus (VSV) infection up-regulated miR-146a expression in mouse macrophages in TLR-myeloid differentiation factor 88-independent but RIG-I-NF-kappaB-dependent manner. In turn, miR-146a negatively regulated VSV-triggered type I IFN production, thus promoting VSV replication in macrophages. In addition to two known miR-146a targets, TRAF6 and IRAK1, we proved that IRAK2 was another target of miR-146a, which also participated in VSV-induced type I IFN production. Furthermore, IRAK1 and IRAK2 participated in VSV-induced type I IFN production by associating with Fas-associated death domain protein, an important adaptor in RIG-I signaling, in a VSV infection-inducible manner. Therefore, we demonstrate that miR-146a, up-regulated during viral infection, is a negative regulator of the RIG-I-dependent antiviral pathway by targeting TRAF6, IRAK1, and IRAK2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases / metabolism*
  • Feedback, Physiological / genetics*
  • Feedback, Physiological / immunology
  • Immunity
  • Interferon Type I / antagonists & inhibitors*
  • Interferon Type I / biosynthesis
  • Interleukin-1 Receptor-Associated Kinases / antagonists & inhibitors
  • Macrophages / drug effects
  • Macrophages / immunology
  • Macrophages / metabolism*
  • Mice
  • MicroRNAs / genetics
  • MicroRNAs / physiology*
  • TNF Receptor-Associated Factor 6 / antagonists & inhibitors
  • Up-Regulation / drug effects
  • Vesicular Stomatitis / genetics
  • Vesicular Stomatitis / immunology
  • Vesiculovirus / drug effects
  • Virus Diseases / genetics
  • Virus Diseases / immunology
  • Virus Replication / drug effects


  • Interferon Type I
  • MicroRNAs
  • Mirn146 microRNA, mouse
  • TNF Receptor-Associated Factor 6
  • Interleukin-1 Receptor-Associated Kinases
  • Irak1 protein, mouse
  • Ddx58 protein, mouse
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases