Unbiased screening identifies regulators of cell-cell adhesion and treatment options in pemphigus.
Humans
Pemphigus
/ metabolism
Cell Adhesion
Desmoglein 3
/ metabolism
Animals
Keratinocytes
/ metabolism
Mice
Kruppel-Like Transcription Factors
/ metabolism
Autoantibodies
/ immunology
Desmosomes
/ metabolism
Disease Models, Animal
Histone Deacetylases
/ metabolism
Gene Expression Regulation
Promoter Regions, Genetic
/ genetics
Male
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
14 Sep 2024
14 Sep 2024
Historique:
received:
23
08
2023
accepted:
15
08
2024
medline:
14
9
2024
pubmed:
14
9
2024
entrez:
13
9
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 39271654
doi: 10.1038/s41467-024-51747-2
pii: 10.1038/s41467-024-51747-2
doi:
Substances chimiques
Desmoglein 3
0
Kruppel-Like Transcription Factors
0
histone deacetylase 3
EC 3.5.1.98
KLF5 protein, human
0
Autoantibodies
0
Histone Deacetylases
EC 3.5.1.98
DSG3 protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
8044Subventions
Organisme : Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (Swiss National Science Foundation)
ID : 197764
Informations de copyright
© 2024. The Author(s).
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