A central role for the armadillo protein plakoglobin in the autoimmune disease pemphigus vulgaris.
In pemphigus vulgaris (PV), autoantibody binding to desmoglein (Dsg) 3 induces loss of intercellular adhesion in skin and mucous membranes. Two hypotheses are currently favored to explain the underlying molecular mechanisms: (a) disruption of adhesion through steric hindrance, and (b) interference of desmosomal cadherin-bound antibody with intracellular events, which we speculated to involve plakoglobin. To investigate the second hypothesis we established keratinocyte cultures from plakoglobin knockout (PG-/-) embryos and PG+/+ control mice. Although both cell types exhibited desmosomal cadherin-mediated adhesion during calcium-induced differentiation and bound PV immunoglobin (IgG) at their cell surface, only PG+/+ keratinocytes responded with keratin retraction and loss of adhesion. When full-length plakoglobin was reintroduced into PG-/- cells, responsiveness to PV IgG was restored. Moreover, in these cells like in PG+/+ keratinocytes, PV IgG binding severely affected the linear distribution of plakoglobin at the plasma membrane. Taken together, the establishment of an in vitro model using PG+/+ and PG-/- keratinocytes allowed us (a) to exclude the steric hindrance only hypothesis, and (b) to demonstrate for the first time that plakoglobin plays a central role in PV, a finding that will provide a novel direction for investigations of the molecular mechanisms leading to PV, and on the function of plakoglobin in differentiating keratinocytes.
Caldelari
R
R
Institute of Animal Pathology, University of Bern, Länggass-Strasse 122, CH-3012 Bern, Switzerland.
de Bruin
A
A
Baumann
D
D
Suter
M M
MM
Bierkamp
C
C
Balmer
V
V
Müller
E
E
D000818:Animals; D051186:Armadillo Domain Proteins; D001323:Autoantibodies / Q000494:pharmacology; D002448:Cell Adhesion / Q000276:immunology; D002454:Cell Differentiation / Q000502:physiology; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000378:metabolism*; D051182:Desmogleins; D051180:Desmoplakins; D003896:Desmosomes / Q000276:immunology / Q000378:metabolism; D029721:Drosophila Proteins; D005333:Fetus / Q000166:cytology; D007074:Immunoglobulin G / Q000494:pharmacology; D019476:Insect Proteins; D015603:Keratinocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D007633:Keratins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010392:Pemphigus / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D015534:Trans-Activators; D051185:gamma Catenin
D051186:Armadillo Domain Proteins; D001323:Autoantibodies; D003598:Cytoskeletal Proteins; D051182:Desmogleins; D051180:Desmoplakins; D029721:Drosophila Proteins; D007074:Immunoglobulin G; D019476:Insect Proteins; D015534:Trans-Activators; D051185:gamma Catenin; D007633:Keratins