title: Plakoglobin-dependent disruption of the desmosomal plaque in pemphigus vulgaris.
abstract: We recently reported that the pathogenesis of pemphigus vulgaris (PV), an autoimmune blistering skin disorder, is driven by the accumulation of c-Myc secondary to abrogation of plakoglobin (PG)-mediated transcriptional c-Myc suppression. PG knock-out mouse keratinocytes express high levels of c-Myc and resemble PVIgG-treated wild-type keratinocytes in most respects. However, they fail to accumulate nuclear c-Myc and loose intercellular adhesion in response to PVIgG-treatment like wild-type keratinocytes. This suggested that PG is also required for propagation of the PVIgG-induced events between augmented c-Myc expression and acantholysis. Here, we addressed this possibility by comparing PVIgG-induced changes in the desmosomal organization between wild-type and PG knock-out keratinocytes. We found that either bivalent PVIgG or monovalent PV-Fab (known to trigger blister formation in vivo) disrupt the linear organization of all major desmosomal components along cell borders in wild-type keratinocytes, simultaneously with a reduction in intercellular adhesive strength. In contrast, PV-Fab failed to affect PG knock-out keratinocytes while PVIgG cross-linked their desmosomal cadherins without significantly affecting desmoplakin. These results identify PG as a principle effector of the PVIgG-induced signals downstream of c-Myc that disrupt the desmosomal plaque at the plasma membrane.
authors.affiliation: Institute of Animal Pathology and DermFocus Vetsuisse Faculty, Berne, Switzerland.
authors.forename: Alain
authors.initials: A
authors.lastname: de Bruin
authors.forename: Reto
authors.initials: R
authors.lastname: Caldelari
authors.forename: Lina
authors.initials: L
authors.lastname: Williamson
authors.forename: Maja M
authors.initials: MM
authors.lastname: Suter
authors.forename: Thomas
authors.initials: T
authors.lastname: Hunziker
authors.forename: Marianne
authors.initials: M
authors.lastname: Wyder
authors.forename: Eliane J
authors.initials: EJ
authors.lastname: Müller
mesh_terms: D000818:Animals; D000918:Antibody Specificity; D002448:Cell Adhesion; D002478:Cells, Cultured; D003432:Cross-Linking Reagents / Q000378:metabolism; D051184:Desmoglein 3 / Q000276:immunology / Q000378:metabolism; D003896:Desmosomes / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology; D007074:Immunoglobulin G / Q000494:pharmacology; D015603:Keratinocytes / Q000473:pathology*; D051379:Mice; D016296:Mutagenesis; D010392:Pemphigus / Q000378:metabolism* / Q000473:pathology*; D051185:gamma Catenin / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D003432:Cross-Linking Reagents; D051184:Desmoglein 3; C495300:Dsg3 protein, mouse; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; C495293:Jup protein, mouse; D051185:gamma Catenin