A central role for the armadillo protein plakoglobin in the autoimmune disease pemphigus vulgaris

In pemphigus vulgaris (PV), autoantibody binding to desmoglein (Dsg) 3 indu ces loss of intercellular adhesion in skin and mucous membranes. Two hypoth eses are currently favored to explain the underlying molecular mechanisms: (a) disruption of adhesion through steric hindrance, and (b) interference o f desmosomal cadherin-bound antibody with intracellular events, which we sp eculated to involve plakoglobin. To investigate the second hypothesis we es tablished keratinocyte cultures from plakoglobin knockout (PG(-/-)) embryos and PG(+/+) control mice. Although both cell types exhibited desmosomal ca dherin-mediated adhesion during calcium-induced differentiation and bound P V immunoglobin (IgG) at their cell surface, only PG(+/+) keratinocytes resp onded with keratin retraction and loss of adhesion. When full-length plakog lobin was reintroduced into PG(-/-) cells, responsiveness to PV IgG was res tored. Moreover, in these cells Pike in PG(+/+) keratinocytes, PV IgG bindi ng severely affected the linear distribution of plakoglobin at the plasma m embrane. 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 plakoglobi n 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 f unction of plakoglobin in differentiating keratinocytes.