Pemphigus Vulgaris Autoantibodies Induce an Endoplasmic Reticulum Stress Response

Desmosomes are intercellular junctions that mediate cell-cell adhesion and are essential for maintaining tissue integrity. Pemphigus vulgaris (PV) is an autoimmune epidermal blistering disease caused by autoantibodies (IgG) targeting desmoglein 3, a desmosomal cadherin. PV autoantibodies cause desmosome disassembly and loss of cell-cell adhesion; however, the molecular signaling pathways that regulate these processes are not fully understood. Using high-resolution time-lapse imaging of live keratinocytes, we found that endoplasmic reticulum (ER) tubules make frequent and persistent contacts with internalizing desmoglein 3 puncta in keratinocytes treated with IgG of patients with PV. Biochemical experiments demonstrated that PV IgG activated ER stress signaling pathways, including both IRE1⍺ and PERK pathways, in cultured keratinocytes. Furthermore, ER stress transcripts were upregulated in the skin of patients with PV. Pharmacological inhibition of ER stress protects against PV IgG-induced desmosome disruption and loss of keratinocyte cell-cell adhesion, suggesting that ER stress may be an important pathomechanism and a therapeutically targetable pathway for PV treatment. These data support a model in which desmosome adhesion is integrated with ER function to serve as a cell adhesion stress sensor that is activated in blistering skin diseases.