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

Henriette Franz, Maitreyi Rathod, Aude Zimmermann, Chiara Stüdle, Vivien Beyersdorfer, Karen Leal-Fischer, Pauline Hanns, Tomás Cunha, Dario Didona, Michael Hertl, Marion Scheibe, Falk Butter, Enno Schmidt and Volker Spindler ()
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Henriette Franz: University of Basel
Maitreyi Rathod: University of Basel
Aude Zimmermann: University of Basel
Chiara Stüdle: University of Basel
Vivien Beyersdorfer: University of Basel
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)
Falk Butter: Institute of Molecular Biology (IMB)
Enno Schmidt: University of Lübeck
Volker Spindler: University of Basel

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-51747-2

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