MicroRNA-146a Feedback Inhibits RIG-I-Dependent Type I IFN Production in Macrophages by Targeting TRAF6, IRAK1, and IRAK2

Citations Over TimeTop 1% of 2009 papers

Abstract

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.

Related Papers

• → Interferon Production and Inhibition of Host Synthesis in Cells Infected with Vesicular Stomatitis Virus(1970)64 cited
• → Persistent infection II. Interferon-inducing temperature-sensitive mutants as mediators of cell sparing: Possible role in persistent infection by vesicular stomatitis virus(1979)63 cited
• → Heterogeneity of the sensitivity of vesicular stomatitis virus to interferons(1977)29 cited
• → Relative Antiviral Resistance Induced in Homologous and Heterologous Cells by Cross-Reacting Interferons(1970)21 cited
• → 5. Analysis of antiviral state in RD114 and A204 cells after interferon treatment(1982)1 cited