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A complex signaling network involving protein kinase CK2 is required for hepatitis C virus core protein-mediated modulation of the iron-regulatory hepcidin gene expression

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Abstract

Hepatitis C virus (HCV) infection is associated with hepatic iron overload and elevated serum iron that correlate to poor antiviral responses. Hepcidin (HAMP), a 25-aa cysteine-rich liver-specific peptide, controls iron homeostasis. Its expression is up-regulated in inflammation and iron excess. HCV-mediated hepcidin regulation remains controversial. Chronic HCV patients possess relatively low hepcidin levels; however, elevated HAMP mRNA has been reported in HCV core transgenic mice and HCV replicon-expressing cells. We investigated the effect of HCV core protein on HAMP gene expression and delineated the complex interplay of molecular mechanisms involved. HCV core protein up-regulated HAMP promoter activity, mRNA, and secreted protein levels. Enhanced promoter activity was abolished by co-transfections of core with HAMP promoter constructs containing mutated/deleted BMP and STAT binding sites. Dominant negative constructs, pharmacological inhibitors, and silencing experiments against STAT3 and SMAD4 confirmed the participation of both pathways in HAMP gene regulation by core protein. STAT3 and SMAD4 expression levels were found increased in the presence of HCV core, which orchestrated SMAD4 translocation into the nucleus and STAT3 phosphorylation. To further understand the mechanisms governing the core effect, the role of the JAK/STAT-activating kinase CK2 was investigated. A CK2-dominant negative construct, a CK2-specific inhibitor, and RNAi interference abrogated the core-induced increase on HAMP promoter activity, mRNA, and protein levels, while CK2 acted in synergy with core to significantly enhance HAMP gene expression. Therefore, HCV core up-regulates HAMP gene transcription via a complex signaling network that requires both SMAD/BMP and STAT3 pathways and CK2 involvement.

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Acknowledgments

We are grateful to Dr. P. Lee (The Scripps Research Institute, USA), Prof. M.U. Muckenthaler (University of Heidelberg, Germany), Dr. J.E. Darnell (Rockefeller University, NY, USA), Dr. R. Derynck (University of California at San Francisco) and Dr. C. Cochet (INSERM U1036, Grenoble, France) for providing promoter constructs and expression plasmids used in this study. Financial support was provided in the context of project 09SYN-12-682, which is implemented under the auspices of NSRF and the National Range Action “COOPERATION” and co-funded by the Greek Government and the European Union - European Regional Development Fund.

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Authors and Affiliations

  1. Laboratory of Molecular Biology and Immunobiotechnology, Department of Biochemistry, Hellenic Pasteur Institute, Athens, Greece

    Pelagia Foka, Alexios Dimitriadis, Eleni Kyratzopoulou, Dionysios A. Giannimaras & Avgi Mamalaki

  2. Laboratory of Molecular Virology, Hellenic Pasteur Institute, Athens, Greece

    Pelagia Foka & Urania Georgopoulou

  3. Department of Biomedical Sciences, University of Padova, Padua, Italy

    Stefania Sarno

  4. Laboratory of Biochemistry, Faculty of Medicine, University of Thessaly, Larissa, Greece

    George Simos

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  1. Pelagia Foka
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  2. Alexios Dimitriadis
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  3. Eleni Kyratzopoulou
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  4. Dionysios A. Giannimaras
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  7. Urania Georgopoulou
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Correspondence to Urania Georgopoulou or Avgi Mamalaki.

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P. Foka and A. Dimitriadis contributed equally to this work and should be regarded as joint first authors.

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Foka, P., Dimitriadis, A., Kyratzopoulou, E. et al. A complex signaling network involving protein kinase CK2 is required for hepatitis C virus core protein-mediated modulation of the iron-regulatory hepcidin gene expression. Cell. Mol. Life Sci. 71, 4243–4258 (2014). https://doi.org/10.1007/s00018-014-1621-4

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  • DOI: https://doi.org/10.1007/s00018-014-1621-4

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