A desmoplakin point mutation insensitive to PKC phosphorylation ameliorates pemphigus vulgaris autoantibody‐mediated loss of cell cohesion (650.4)

Abstract

Desmoplakin (DP) serves to anchor intermediate filaments in desmosomal complexes. Recent data suggest that a specific DP point mutation (S2849G) exhibits increased keratin filament association and fosters Ca2+‐insensitivity of desmosomes in keratinocytes, presumably by rendering DP inaccessible for PKC phosphorylation. Previously, we have shown that depletion of the desmosomal adhesion molecule desmoglein 3 (Dsg3) induced by autoantibodies from patients with the blistering skin disease pemphigus vulgaris (PV‐IgG) is reduced in maturated desmosomes and dependent on PKC signaling. Thus, we investigated the role of DP‐S2849G for loss of cell cohesion mediated by PV‐IgG. In cell dissociation assays, expression of DP‐S2849G increased cell cohesion in two different human keratinocyte cell lines and ameliorated loss of cell adhesion induced by PV‐IgG or treatment with AK23, a pathogenic Dsg3 antibody derived from a pemphigus mouse model. Depletion of Dsg3 was inhibited by DP‐S2849G in the cytoskeletal (Triton‐X 100 insoluble) fraction and keratin filament retraction, a hallmark of PV, was efficiently blocked. In line with this, DP was phosphorylated upon incubation with PV‐IgG in a PKC‐dependent manner. Taken together, our data demonstrate the relevance of keratin filament anchorage to desmosomes for cell adhesion and suggest PKC‐mediated DP phosphorylation as a central mechanism in PV pathogenesis.