Pemphigus autoantibodies identify a desmoglein 3/p38MAPK adhesion complex regulating keratinocyte cohesion

Abstract

Loss of cell adhesion in the autoimmune blistering skin disease pemphigus vulgaris is mediated by autoantibodies targeting the desmosomal cadherins desmoglein (Dsg)3 and Dsg1. We recently demonstrated a Dsg‐cosslinking peptide (TP) to protect against autoantibody‐mediated cell dissociation in vitro and in vivo by promoting interaction of Dsg molecules and inhibiting the activation of p38MAPK. Here, we used TP to further characterize the mechanisms underlying loss of cell adhesion via desmoglein signaling. Interference with Dsg interaction by tryptophan or AK23, a Dsg3 antibody from a pemphigus mouse model, induced cell dissociation as well as p38MAPK activation, indicating loss of Dsg binding to be a trigger for intracellular signaling. Upon incubation with AK23, immunoprecipitation and proximity ligation assays revealed rapid phosphorylation of p38MAPK associated with Dsg3, which was blocked by TP incubation. Similar to inhibition of p38MAPK by SB202190, TP prevented AK23‐induced keratin filament retraction, a hallmark of pemphigus, and promoted oligomerization of Dsg3 within desmosomes. Taken together, these data indicate for the first time that a disease‐relevant adhesion‐dependent signaling complex consisting of Dsg3 and p38MAPK exists which regulates cell cohesion via keratin filament reorganization.