Abstract
Coxsackievirus B3 (CVB3) is one of the most prevalent causes of viral myocarditis and is associated with many other pathological conditions. CVB3 replication relies on host cellular machineries and causes direct damage to host cells. MicroRNAs have been found to regulate viral infections but their roles in CVB3 infection are still poorly understood. Here we describe a novel mechanism by which miR-126 regulates two signal pathways essential for CVB3 replication. We found that CVB3-induced ERK1/2 activation triggered the phosphorylation of ETS-1 and ETS-2 transcription factors, which induced miR-126 upregulation. By using both microRNA mimics and inhibitors, we proved that the upregulated miR-126 suppressed sprouty-related, EVH1 domain containing 1 (SPRED1) and in turn enhanced ERK1/2 activation. This positive feedback loop of ERK1/2-miR-126-ERK1/2 promoted CVB3 replication. Meanwhile, miR-126 expression stimulated GSK-3β activity and induced degradation of β-catenin through suppressing LRP6 and WRCH1, two newly identified targets in the Wnt/β-catenin pathway, which sensitized the cells to virus-induced cell death and increased viral progeny release to initiate new infections. Our results demonstrate that upregulated miR-126 upon CVB3 infection targets SPRED1, LRP6, and WRCH1 genes, mediating cross-talk between ERK1/2 and Wnt/β-catenin pathways, and thus promoting viral replication and contributes to the viral cytopathogenicity.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3' Untranslated Regions / genetics
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Adaptor Proteins, Signal Transducing
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Base Sequence
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Blotting, Western
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Cell Line
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Cells, Cultured
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Enterovirus B, Human / genetics*
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Enterovirus B, Human / physiology
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Glycogen Synthase Kinase 3 / genetics
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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HeLa Cells
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Humans
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism
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Low Density Lipoprotein Receptor-Related Protein-6 / genetics
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Low Density Lipoprotein Receptor-Related Protein-6 / metabolism
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MAP Kinase Signaling System / genetics*
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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MicroRNAs / genetics*
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MicroRNAs / metabolism
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Phosphorylation
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Proto-Oncogene Protein c-ets-1 / genetics
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Proto-Oncogene Protein c-ets-1 / metabolism
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Proto-Oncogene Protein c-ets-2 / genetics
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Proto-Oncogene Protein c-ets-2 / metabolism
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RNA Interference
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Reverse Transcriptase Polymerase Chain Reaction
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Sequence Homology, Nucleic Acid
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Virus Replication*
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Wnt Signaling Pathway / genetics*
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beta Catenin / genetics*
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beta Catenin / metabolism
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rho GTP-Binding Proteins / genetics
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rho GTP-Binding Proteins / metabolism
Substances
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3' Untranslated Regions
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Adaptor Proteins, Signal Transducing
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ETS1 protein, human
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ETS2 protein, human
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Intracellular Signaling Peptides and Proteins
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LRP6 protein, human
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Low Density Lipoprotein Receptor-Related Protein-6
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MIRN126 microRNA, human
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Membrane Proteins
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MicroRNAs
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Proto-Oncogene Protein c-ets-1
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Proto-Oncogene Protein c-ets-2
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SPRED1 protein, human
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beta Catenin
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GSK3B protein, human
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Glycogen Synthase Kinase 3 beta
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Glycogen Synthase Kinase 3
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RHOU protein, human
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rho GTP-Binding Proteins