Abstract
Impairment of desmosomal cell-cell adhesion leads to life-threatening diseases, such as the autoimmune skin-blistering disorder pemphigus vulgaris (PV). Disease management strategies that stabilize intercellular adhesion, in addition to the existing immunosuppression therapies, may result in improved clinical outcomes. Previous findings showed that the serine protease inhibitor SERPINB5 promotes intercellular adhesion by binding to and regulating the localization of the desmosomal adapter molecule desmoplakin (DSP) at the plasma membrane. We here show that SERPINB5 overexpression prevents PV-IgG–mediated loss of cell-cell adhesion and DSP dissociation from the cell membrane. We mechanistically demonstrate that SERPINB5 loss deregulates TGF-β signaling, a pathway known to destabilize DSP in keratinocytes. TGF-β signaling was also activated in skin biopsies of patients with PV and keratinocytes treated with PV autoantibodies, suggesting a contribution to disease. Inhibition of TGF-β signaling ameliorated PV-IgG–mediated loss of cell-cell adhesion, increased DSP membrane expression, and prevented PV-IgG–induced blister formation in a human ex vivo skin model. Together, SERPINB5 modulates DSP and intercellular adhesion through the regulation of TGF-β signaling. Further, TGF-β signaling was identified as a potential target for pemphigus treatment.
Authors
Maitreyi Rathod, Mariam Petrosyan, Aude Zimmermann, Maike Märker, Tobias Gosau, Henriette Franz, Tomás Cunha, Dario Didona, Michael Hertl, Enno Schmidt, Volker Spindler
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