MiR-125b-5p promotes pemphigus vulgaris pathogenesis by modulating desmosome structures.

Pemphigus vulgaris (PV) is a life-threatening autoimmune bullous disease with an unclear pathogenesis. Our previous study indicated that the expression of miR-125b-5p was significantly elevated in PV patients. MiR-125b-5p has been reported to target P63 mRNA and inhibit the expression of P63, while p53-apoptosis-effector-related-to-PMP-22 (PERP) is a downstream protein regulated by P63. However, the role and underlying molecular mechanisms of miR-125b-5p in PV remain unclear. Here, we explored the roles of miR-125b-5p, P63, and PERP in regulating desmosome integrity and their contribution to PV pathogenesis. The dual-luciferase reporter assay showed that miR-125b-5p inhibited P63 expression by directly binding to the 3' UTR of P63 mRNA. Mouse tongue tissues were cultured in vitro and treated with desmoglein (Dsg) 3-monoclonal antibody (mAb) or with miR-125b-5p overexpression before Dsg3-mAb treatment. Overexpression of miR-125b-5p significantly reduced the mRNA and protein levels of P63 and PERP in Dsg3-mAb-treated tongue tissue. Transmission electron microscopy analysis of the structure of desmosomes revealed that, in tongue tissue with miR-125b-5p overexpression and Dsg3-mAb treatment, the interdesmosal width was significantly increased, the thickness of keratin insertion into the membrane was markedly reduced, and the desmosome structures exhibited evident damage. Together, these findings indicate that miR-125b-5p reduced the expression of both P63 and PERP by targeting P63, thereby contributing to the disruption of desmosome integrity.