Desmoglein-driven dynamic signaling in pemphigus vulgaris: a systematic review of pathogenic pathways

Epithelial tissue integrity is maintained through specialized intercellular junctions known to coordinate homeostatic processes. In this context, outside-in signaling and mechanotransduction through desmosomal cadherins, the building blocks of desmosomes and main stress bearers in epithelial tissue, are only starting to emerge. To better understand the dual function of desmosomal cadherins in structural integrity and cellular signaling, we here performed a systematic, unbiased review on pathogenic signaling effectors identified in models and patients with pemphigus vulgaris (PV). PV is an autoimmune blistering disorder characterized by disruption of desmosomal transadhesion through autoantibodies mainly targeting the desmosomal cadherins desmoglein (Dsg) 3 or Dsg1 and Dsg3. The survey of functionally validated pathogenic pathways published since inception in 1977 up to mid-2024 identifies 128 studies and 128 signaling molecules, highlighting a coherent network of biomechanical, bioelectrical, and biochemical signaling events. This in-depth analysis will stimulate future research as well as development of potential therapeutic applications beyond PV.