Electron microscopy reveals that phospholipase C and Ca(2' )signaling regulate keratin filament uncoupling from desmosomes in Pemphigus

Egu, Desalegn T.; Schmitt, Thomas; Sigmund, Anna M. und Waschke, Jens (2022): Electron microscopy reveals that phospholipase C and Ca(2' )signaling regulate keratin filament uncoupling from desmosomes in Pemphigus. In: Annals of Anatomy - Anatomischer Anzeiger, Bd. 241, 151904

Abstract

Pemphigus vulgaris (PV) is a severe autoimmune blistering skin disease caused primarily by autoantibodies (PV-IgG) against the desmosomal cadherins desmoglein (Dsg) 1 and Dsg 3. Pemphigus is a model disease to study desmosome regulation because patient lesions are characterized by ultrastructural hallmarks including loss, shrinkage and splitting of desmosomes as well as by retraction of keratin filaments. The mechanisms underlying the disease are not completely understood but involve several intracellular signaling pathways triggered by autoantibody binding. Recently, we demonstrated that PhosphoinositidPhospholipase C (PLC) and Ca2' signaling are required for acantholysis in human epidermis. Here, we used transmission electron microscopy to characterize the role of PLC and Ca2' signaling with regard to the pathogenic effects of PV-IgG on desmosome ultrastructure in human ex vivo skin model. First, we observed that the PV-IgG used in this study significantly reduced desmosome length and caused uncoupling of desmosomes from keratin filaments. Moreover, PV-IgG enhanced the number of split desmosomes but did not cause a significant loss of desmosomes. We found that inhibition of PLC and Ca2' signaling significantly blocked keratin filament uncoupling but not shrinkage of desmosomes. Blocking Ca2' flux prevented desmosome splitting. The ultrastructural analysis revealed that for preventing skin blistering it is sufficient to enhance keratin filament insertion, which is regulated by PLC/ Ca2'. Here, we underscore the unique role of electron microscopy to investigate the underlying mechanisms by which a signaling pathway regulates desmosome ultrastructure in pemphigus.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0940-9602
• Sprache: Englisch