097 VDAC as a novel actionable therapeutic target in pemphigus vulgaris

Pemphigus vulgaris (PV), a severe mucocutaneous blistering disease, results from autoantibody-mediated destabilization of epidermal cell-cell adhesion. A functional risk variant at the ST18 locus was found to promote expression. Increased expression aggravate deleterious effect PV autoantibodies in part through induction p53-mediated pro-apoptotic pathways. Global RNA sequencing human keratinocytes (KCs) overexpressing showed: (1) upregulation VDAC1-3 which encode voltage-dependent anion channel (VDAC) protein, key regulator mitochondria-mediated apoptosis; (2) down-regulation BCL2 encoding anti-apoptotic protein Bcl-2. Of interest, mitochondrial VDAC and p53 antagonize Bcl-2 activity. In line with RNAseq data, immunostaining skin biopsies obtained patients revealed dramatically increased Recently, oligomerization inhibitor VBIT-12 has been suggested as novel therapeutics for autoimmune diseases. KCs exposed AK23, pathogenic anti-desmoglein 3 antibody, ST18, exhibited elevated apoptotic activity attested by significantly caspase 3/7 TUNEL staining. robustly attenuated this response concomitantly led seen immunoblotting, transcriptional shown luciferase reporter assay. This that inhibition overexpressed prevents disadhesion PV. Substantiating hypothesis, efficiently prevent acantholysis due IgG/AK23 dispase dissociation conclusion, our findings identify factor pathogenesis thus an innovative attractive therapeutic target treatment disease.