Abstract
Upon immune recognition of viruses, the mammalian innate immune response activates a complex signal transduction network to combat infection. This activation requires phosphorylation of key transcription factors regulating IFN production and signaling, including IFN regulatory factor 3 (IRF3) and STAT1. The mechanisms regulating these STAT1 and IRF3 phosphorylation events remain unclear. Here, using human and mouse cell lines along with gene microarrays, quantitative RT-PCR, viral infection and plaque assays, and reporter gene assays, we demonstrate that a microRNA cluster conserved among bilaterian animals, encoding miR-96, miR-182, and miR-183, regulates IFN signaling. In particular, we observed that the miR-183 cluster promotes IFN production and signaling, mediated by enhancing IRF3 and STAT1 phosphorylation. We also found that the miR-183 cluster activates the IFN pathway and inhibits vesicular stomatitis virus infection by directly targeting several negative regulators of IRF3 and STAT1 activities, including protein phosphatase 2A (PPP2CA) and tripartite motif-containing 27 (TRIM27). Overall, our work reveals an important role of the evolutionarily conserved miR-183 cluster in the regulation of mammalian innate immunity.
Highlights
Upon immune recognition of viruses, the mammalian innate immune response activates a complex signal transduction network to combat infection
We found that the miR-183 cluster activates the IFN pathway and inhibits vesicular stomatitis virus infection by directly targeting several negative regulators of IFN regulatory factor 3 (IRF3) and STAT1 activities, including protein phosphatase 2A (PPP2CA) and tripartite motif– containing 27 (TRIM27)
Interferons induce the expression of numerous antiviral effector proteins, and IFN production relies on multiple phosphorylation events, including C-terminal phosphorylation of IFN regulatory factor 3 (IRF3) [2, 3], a transcription factor that regulates the expression of both type I and III IFNs [4]
Summary
Upon immune recognition of viruses, the mammalian innate immune response activates a complex signal transduction network to combat infection. This activation requires phosphorylation of key transcription factors regulating IFN production and signaling, including IFN regulatory factor 3 (IRF3) and STAT1. Our work reveals an important role of the evolutionarily conserved miR-183 cluster in the regulation of mammalian innate immunity. Genetic variation in this miRNA cluster is associated with increased susceptibility to inflammatory and autoimmune disease [16] Despite these connections, the role of the miR-183 cluster in innate immunity is unclear. We found that all three miRNAs encoded in the cluster promoted IFN signaling and production through repression of key negative regulators of IRF3 and STAT1 signaling. Our work demonstrates a novel role of this miRNA cluster in cooperative regulation of the IFN pathway
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