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bioRxiv · 10.1101/2024.10.15.618475

SERPINB5-TGF-β signalling modulates desmoplakin membrane localization and ameliorates pemphigus vulgaris skin blistering

Rathod, M.·Zimmermann, A.·Franz, H.·Cunha, T.·Didona, D.·Hertl, M.·Schmidt, E.·Spindler, V.
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Abstract

Impairment of desmosomal cell-cell adhesion leads to several 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 the loss of DSP from the cell membrane. We mechanistically demonstrate that SERPINB5 loss deregulates TGF-{beta} signalling, a pathway known to destabilize DSP in keratinocytes. TGF-{beta} signalling was also activated in skin biopsies of PV patients and keratinocytes treated with PV autoantibodies, suggesting a contribution to disease. Inhibition of TGF-{beta} activation 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-{beta} signalling. Further, TGF-{beta} signalling was identified as a potential target for pemphigus treatment.

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Rathod, M., Zimmermann, A., Franz, H., Cunha, T., Didona, D., Hertl, M., Schmidt, E., Spindler, V.. 2024-10-15. SERPINB5-TGF-β signalling modulates desmoplakin membrane localization and ameliorates pemphigus vulgaris skin blistering. https://doi.org/10.1101/2024.10.15.618475

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