1347 Desmoglein-3 acts as an anti-stress protein via suppression of p53

Abstract

Desmoglein-3 (Dsg3), the pemphigus vulgaris antigen (PVA), plays an important role in keratinocyte cell-cell adhesion and maintenance of tissue integrity. Recent studies have shown that Dsg3 functions as a signaling molecule regulating various pathways with demonstrable cancer-associations. Many of these pathways also have been implicated in PV. Importantly, our preliminary data suggest that Dsg3 may play a role in the suppression of p53, a key transcription factor that governs cell growth, apoptosis and senescence in response to various stresses. The present study investigated this pathway in keratinocytes (harboring wtp53) subjected to UV and mechanical stretching, and to explore its contribution to the pathogenesis of PV. We showed that Dsg3 knockdown caused increased expression and stabilization of p53 (with half-life >3-fold compared to control), and its activity in cells exposed to UV and cyclic strain. This result was consistent with findings from Dsg3 gain-of-function studies showing suppression of p53 and downstream p21/Bax in response to stress signals. Analysis of clinical specimens detected increased p53 in 12 of 25 PV patient samples, with diffuse cytoplasmic and nuclear staining in cells surrounding the blisters. Treatment of keratinocytes with PV sera evoked pronounced p53 expression in both the nucleus and cytoplasm of cells. Furthermore, we established that this Dsg3-p53 pathway involved YAP since Dsg3 knockdown resulted in marked reduction of YAP/pYAP with the binding of Dsg3/YAP being detectable. Evident increased nuclear YAP also was detected in PV keratinocytes. In summary, our findings establish a novel role for Dsg3 serving as an anti-stress protein, via suppression of p53, and identify an unprecedented interaction of this pathway with YAP in controlling skin homeostasis.