Pemphigus vulgaris (PV) is a life-threatening autoimmune mucocutaneous blistering disease caused by auto-antibodies directed against various desmosomal components such as desmoglein 3. Variants in the ST18 gene predispose to PV. ST18 overexpression was recently shown to promote PV IgG-induced cell-cell disadhesion, in part through activation of pro-apoptotic pathways which were independently found to contribute to PV IgG-induced blister formation. Using RNA-seq, we now show that overexpression of ST18 in human keratinocytes is associated with up-regulation of the VDAC1-3 genes, which encode the voltage-dependent anion channel (VDAC) protein. VDAC mediates metabolic cross-talk between mitochondria and the rest of the cell and serves as a pivotal regulator of mitochondria-mediated apoptosis. In line with the RNA-seq data, we observed by immunohistochemistry increased VDAC1 expression in the epidermis of PV patients as compared to healthy controls. We, therefore aimed at delineating the effects of the VDAC oligomerization inhibitor, VBIT-12, on PV phenotype. Keratinocytes exposed to AK23 (an anti-desmoglein 3 antibody) and overexpressing ST18 displayed elevated apoptotic activity as assessed by caspase 3/7 activity and TUNEL assays. VBIT-12 strongly attenuated this response. We then ascertained the effect of VBIT-12 on PV IgG-induced acantholysis using the dispase dissociation assay in keratinocytes expressing normal and high levels of ST18. VBIT-12 was found to restore cell-cell adhesion stability in keratinocytes exposed to anti-desmoglein 3 antibodies, even in the face of ST18 overexpression. Taken collectively, these observations reveal a novel patho-mechanism underlying, at least in part, the deleterious effect of ST18 on cell-cell adhesion, suggesting the possibility to attenuate PV clinical manifestations through VDAC inhibition.

LB048 - ST18-induced VDAC as a novel therapeutic target in pemphigus vulgaris

The scientific meeting of the European Society for Dermatological Research (ESDR) is held yearly, usually in September. With an international attendance of more than 1000 skin scientists from around the globe, the four-day event includes short oral presentations from peer-reviewed abstracts, keynote lectures from international experts, sponsored symposia, satellite programs, educational events as well as an important focus on posters, networking and building collaborations amongst scientists. For more information about this year’s meeting visit our website.