Desmosomal interactome in keratinocytes: a systems biology approach leading to an understanding of the pathogenesis of skin disease.

We provide the first description of the desmosome network in keratinocytes using a systems level approach. The desmo-adhesome consists of 59 proteins connected by 128 direct interactions and forms different functional subnets. Whilst the structure appears to be extremely robust against random perturbations, network fragmentation analysis suggests that the desmo-adhesome is susceptible to targeted attacks. To confirm this prediction, we applied this model to the autoimmune disease Pemphigus Vulgaris (PV), a paradigm of external perturbation of the desmosome. Our analysis showed that the adaptor protein plakophilin (Pkp) 3 was in the highest percentile group for both connectivity rate and gene expression changes in experimental PV. This observation led us to speculate that Pkp3 was crucial in desmosomal remodelling, and therefore we designed the experiments to verify this hypothesis. Our data demonstrate that, whilst Pkp3 is important in conferring adhesive strength to keratinocytes, it also acts as a central molecule mediating cell-cell detachment induced by PV IgG.