Desmosomal cadherin tension loss in pemphigus vulgaris mediated by the inhibition of active RhoA at cell-cell adhesions.

Autoantibody binding to keratinocyte surface antigens, primarily desmoglein 3 (Dsg3) in the desmosome, leads to dissociation of cell-cell adhesions in pemphigus vulgaris. Much of the biophysical transformations after antibody binding remain underexplored. It is unclear how tensions in desmosomes and cell-cell adhesion structures change in response to antibodies, and how the altered tensional states translate to cellular responses. Here, using fluorescence resonance energy transfer-based tension sensors and traction force microscopy, we observed tension loss at Dsg3 and the entire cell-cell adhesion after antibody binding, along with potentially compensatory increase in junctional traction force at cell-extracellular matrix adhesions. Our data also indicate that this tension loss is mediated by RhoA inhibition at cell-cell contacts and can be partially restored by altering cell contractility. Collectively, these findings shed light on the biophysical mechanisms governing cell-cell interactions under autoimmune conditions, and may lead to therapies aimed at restoring tensional balance at cell-cell adhesions.