# SERPINB5/TGF-β signaling modulates desmoplakin membrane localization and ameliorates pemphigus vulgaris skin blistering

## TL;DR

This study shows how SERPINB5 helps prevent skin blistering in pemphigus vulgaris by regulating TGF-β signaling and stabilizing cell adhesion.

## Contribution

The study reveals a novel mechanism linking SERPINB5, TGF-β signaling, and desmoplakin in pemphigus vulgaris.

## Key findings

- SERPINB5 overexpression prevents PV-IgG–mediated loss of cell-cell adhesion and DSP dissociation.
- TGF-β signaling is activated in PV patients and contributes to disease progression.
- Inhibiting TGF-β signaling reduces blister formation in a human ex vivo skin model.

## 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.

We show SERPINB5 modulates DSP and intercellular adhesion through the regulation of TGF-β signalling, which was identified as a potential target for pemphigus treatment.