Cellular and Molecular Life Sciences

, Volume 70, Issue 23, pp 4631–4644

MiR-126 promotes coxsackievirus replication by mediating cross-talk of ERK1/2 and Wnt/β-catenin signal pathways

  • Xin Ye
  • Maged Gomaa Hemida
  • Ye Qiu
  • Paul J. Hanson
  • Huifang Mary Zhang
  • Decheng Yang
Research Article

DOI: 10.1007/s00018-013-1411-4

Cite this article as:
Ye, X., Hemida, M.G., Qiu, Y. et al. Cell. Mol. Life Sci. (2013) 70: 4631. doi:10.1007/s00018-013-1411-4
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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.

Keywords

CVB3 Myocarditis MiR-126 ERK1/2 Wnt

Supplementary material

18_2013_1411_MOESM1_ESM.pdf (1.1 mb)
Supplementary material 1 (PDF 1088 kb)

Copyright information

© Springer Basel 2013

Authors and Affiliations

  • Xin Ye
    • 1
  • Maged Gomaa Hemida
    • 1
  • Ye Qiu
    • 1
  • Paul J. Hanson
    • 1
  • Huifang Mary Zhang
    • 1
  • Decheng Yang
    • 1
  1. 1.Department of Pathology and Laboratory Medicine, The Institute for Heart and Lung Health, St. Paul’s HospitalUniversity of British ColumbiaVancouverCanada