1. ST18 affects cell–cell adhesion in pemphigus vulgaris in a tumour necrosis factor‐α‐dependent fashion*
- Author
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Sari Assaf, K. Malovitski, Alon Peled, L. Malki, Eli Sprecher, M. Pavlovsky, T. Mayer, Dan Vodo, Ofer Sarig, and J. Mohamad
- Subjects
Keratinocytes ,Cell ,Dermatology ,Proinflammatory cytokine ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Cell Adhesion ,medicine ,Humans ,Promoter Regions, Genetic ,Cell adhesion ,Transcription factor ,Autoantibodies ,Desmoglein 3 ,Tumor Necrosis Factor-alpha ,Chemistry ,Pemphigus vulgaris ,Promoter ,medicine.disease ,Molecular biology ,Repressor Proteins ,medicine.anatomical_structure ,Tumor necrosis factor alpha ,Chromatin immunoprecipitation ,Pemphigus - Abstract
Background Pemphigus vulgaris (PV) is a life-threatening mucocutaneous autoimmune blistering disease. We previously showed that genetic variants within the ST18 gene promoter area confer a sixfold increase in the propensity to develop PV. ST18, a transcription factor, was found to be overexpressed in the epidermis of patients with PV. In addition, it was found to promote autoantibody-mediated abnormal epidermal cell-cell adhesion and secretion of proinflammatory mediators by keratinocytes. Objectives To delineate the mechanism through which ST18 contributes to destabilization of cell-cell adhesion. Methods We used quantitative reverse-transcriptase polymerase chain reaction, immunofluorescence microscopy, a luciferase reporter system, site-directed mutagenesis, chromatin immunoprecipitation (ChIP) and the dispase dissociation assay. Results The ChIP and luciferase reporter assays showed that ST18 directly binds and activates the TNF promoter. Accordingly, increased ST18 expression contributes to PV pathogenesis by destabilizing cell-cell adhesion in a tumour necrosis factor (TNF)-α-dependent fashion. In addition, dual immunofluorescence staining showed increased expression of both ST18 and TNF-α in the skin of patients with PV carrying an ST18-associated PV risk variant, which was found to be associated with a more extensive PV phenotype. Conclusions Our findings suggest a role for TNF-α in mediating the deleterious effect of increased ST18 expression in PV skin.
- Published
- 2021