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Unbiased screening identifies regulators of cell-cell adhesion and treatment options in pemphigus

Author

Listed:
  • Henriette Franz

    (University of Basel)

  • Maitreyi Rathod

    (University of Basel
    University Medical Center Hamburg Eppendorf (UKE))

  • Aude Zimmermann

    (University of Basel)

  • Chiara Stüdle

    (University of Basel
    University of Bern)

  • Vivien Beyersdorfer

    (University of Basel
    University Medical Center Hamburg Eppendorf (UKE))

  • Karen Leal-Fischer

    (University of Basel)

  • Pauline Hanns

    (University of Basel)

  • Tomás Cunha

    (Philipps-Universität Marburg)

  • Dario Didona

    (Philipps-Universität Marburg)

  • Michael Hertl

    (Philipps-Universität Marburg)

  • Marion Scheibe

    (Institute of Molecular Biology (IMB)
    Friedrich-Loeffler-Institute)

  • Falk Butter

    (Institute of Molecular Biology (IMB)
    Friedrich-Loeffler-Institute)

  • Enno Schmidt

    (University of Lübeck)

  • Volker Spindler

    (University of Basel
    University Medical Center Hamburg Eppendorf (UKE))

Abstract

Cell-cell junctions, and specifically desmosomes, are crucial for robust intercellular adhesion. Desmosomal function is compromised in the autoimmune blistering skin disease pemphigus vulgaris. We combine whole-genome knockout screening and a promotor screen of the desmosomal gene desmoglein 3 in human keratinocytes to identify novel regulators of intercellular adhesion. Kruppel-like-factor 5 (KLF5) directly binds to the desmoglein 3 regulatory region and promotes adhesion. Reduced levels of KLF5 in patient tissue indicate a role in pemphigus vulgaris. Autoantibody fractions from patients impair intercellular adhesion and reduce KLF5 levels in in vitro and in vivo disease models. These effects were dependent on increased activity of histone deacetylase 3, leading to transcriptional repression of KLF5. Inhibiting histone deacetylase 3 increases KLF5 levels and protects against the deleterious effects of autoantibodies in murine and human pemphigus vulgaris models. Together, KLF5 and histone deacetylase 3 are regulators of desmoglein 3 gene expression and intercellular adhesion and represent potential therapeutic targets in pemphigus vulgaris.

Suggested Citation

  • Henriette Franz & Maitreyi Rathod & Aude Zimmermann & Chiara Stüdle & Vivien Beyersdorfer & Karen Leal-Fischer & Pauline Hanns & Tomás Cunha & Dario Didona & Michael Hertl & Marion Scheibe & Falk Butt, 2024. "Unbiased screening identifies regulators of cell-cell adhesion and treatment options in pemphigus," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51747-2
    DOI: 10.1038/s41467-024-51747-2
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    References listed on IDEAS

    as
    1. Anna M. Sigmund & Markus Winkler & Sophia Engelmayer & Daniela Kugelmann & Desalegn T. Egu & Letyfee S. Steinert & Michael Fuchs & Matthias Hiermaier & Mariya Y. Radeva & Franziska C. Bayerbach & Elis, 2023. "Author Correction: Apremilast prevents blistering in human epidermis and stabilizes keratinocyte adhesion in pemphigus," Nature Communications, Nature, vol. 14(1), pages 1-1, December.
    2. Oxana Nekrasova & Robert M. Harmon & Joshua A. Broussard & Jennifer L. Koetsier & Lisa M. Godsel & Gillian N. Fitz & Margaret L. Gardel & Kathleen J. Green, 2018. "Desmosomal cadherin association with Tctex-1 and cortactin-Arp2/3 drives perijunctional actin polymerization to promote keratinocyte delamination," Nature Communications, Nature, vol. 9(1), pages 1-18, December.
    3. Anna M. Sigmund & Markus Winkler & Sophia Engelmayer & Daniela Kugelmann & Desalegn T. Egu & Letyfee S. Steinert & Michael Fuchs & Matthias Hiermaier & Mariya Y. Radeva & Franziska C. Bayerbach & Elis, 2023. "Apremilast prevents blistering in human epidermis and stabilizes keratinocyte adhesion in pemphigus," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
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