Unbiased screening identifies regulators of cell-cell adhesion and treatment options in pemphigus
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Unbiased screening identifies regulators of cell-cell adhesion and treatment options in pemphigus. / Franz, Henriette; Rathod, Maitreyi; Zimmermann, Aude; Stüdle, Chiara; Beyersdorfer, Vivien; Leal-Fischer, Karen; Hanns, Pauline; Cunha, Tomás; Didona, Dario; Hertl, Michael; Scheibe, Marion; Butter, Falk; Schmidt, Enno; Spindler, Volker.
In: NAT COMMUN, Vol. 15, No. 1, 14.09.2024, p. 8044.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Unbiased screening identifies regulators of cell-cell adhesion and treatment options in pemphigus
AU - Franz, Henriette
AU - Rathod, Maitreyi
AU - Zimmermann, Aude
AU - Stüdle, Chiara
AU - Beyersdorfer, Vivien
AU - Leal-Fischer, Karen
AU - Hanns, Pauline
AU - Cunha, Tomás
AU - Didona, Dario
AU - Hertl, Michael
AU - Scheibe, Marion
AU - Butter, Falk
AU - Schmidt, Enno
AU - Spindler, Volker
N1 - © 2024. The Author(s).
PY - 2024/9/14
Y1 - 2024/9/14
N2 - 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.
AB - 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.
KW - Humans
KW - Pemphigus/metabolism
KW - Cell Adhesion
KW - Desmoglein 3/metabolism
KW - Animals
KW - Keratinocytes/metabolism
KW - Mice
KW - Kruppel-Like Transcription Factors/metabolism
KW - Autoantibodies/immunology
KW - Desmosomes/metabolism
KW - Disease Models, Animal
KW - Histone Deacetylases/metabolism
KW - Gene Expression Regulation
KW - Promoter Regions, Genetic/genetics
KW - Male
U2 - 10.1038/s41467-024-51747-2
DO - 10.1038/s41467-024-51747-2
M3 - SCORING: Journal article
C2 - 39271654
VL - 15
SP - 8044
JO - NAT COMMUN
JF - NAT COMMUN
SN - 2041-1723
IS - 1
ER -