A novel Nrf2-miR-29-desmocollin-2 axis regulates desmosome function in keratinocytes

Svitlana Kurinna, Matthias Schäfer, Paola Ostano, Emmanuel Karouzakis, Giovanna Chiorino, Wilhelm Bloch, Andreas Bachmann, Steffen Gay, David Garrod, Karine Lefort, Gian-Paolo Dotto, Hans-Dietmar Beer and Sabine Werner ()
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Svitlana Kurinna: Institute of Molecular Health Sciences, ETH Zurich
Matthias Schäfer: Institute of Molecular Health Sciences, ETH Zurich
Paola Ostano: Laboratory of Cancer Genomics, Fondazione Edo ed Elvo Tempia
Emmanuel Karouzakis: Center of Experimental Rheumatology, University Hospital Zurich
Giovanna Chiorino: Laboratory of Cancer Genomics, Fondazione Edo ed Elvo Tempia
Wilhelm Bloch: German Sport University Cologne
Andreas Bachmann: Institute of Molecular Health Sciences, ETH Zurich
Steffen Gay: Center of Experimental Rheumatology, University Hospital Zurich
David Garrod: Faculty of Life Sciences, University of Manchester
Karine Lefort: University of Lausanne
Gian-Paolo Dotto: University of Lausanne
Hans-Dietmar Beer: University Hospital Zurich
Sabine Werner: Institute of Molecular Health Sciences, ETH Zurich

Nature Communications, 2014, vol. 5, issue 1, 1-13

Abstract: Abstract The Nrf2 transcription factor controls the expression of genes involved in the antioxidant defense system. Here, we identified Nrf2 as a novel regulator of desmosomes in the epidermis through the regulation of microRNAs. On Nrf2 activation, expression of miR-29a and miR-29b increases in cultured human keratinocytes and in mouse epidermis. Chromatin immunoprecipitation identified the Mir29ab1 and Mir29b2c genes as direct Nrf2 targets in keratinocytes. While binding of Nrf2 to the Mir29ab1 gene activates expression of miR-29a and -b, the Mir29b2c gene is silenced by DNA methylation. We identified desmocollin-2 (Dsc2) as a major target of Nrf2-induced miR-29s. This is functionally important, since Nrf2 activation in keratinocytes of transgenic mice causes structural alterations of epidermal desmosomes. Furthermore, the overexpression of miR-29a/b or knockdown of Dsc2 impairs the formation of hyper-adhesive desmosomes in keratinocytes, whereas Dsc2 overexpression has the opposite effect. These results demonstrate that a novel Nrf2-miR-29-Dsc2 axis controls desmosome function and cutaneous homeostasis.

Date: 2014
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DOI: 10.1038/ncomms6099

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