Abstract
Desmoglein-3 (Dsg3), the Pemphigus Vulgaris (PV) antigen (PVA), plays an essential role in keratinocyte cell–cell adhesion and regulates various signaling pathways involved in the progression and metastasis of cancer where it is upregulated. We show here that expression of Dsg3 impacts on the expression and function of p53, a key transcription factor governing the responses to cellular stress. Dsg3 depletion increased p53 expression and activity, an effect enhanced by treating cells with UVB, mechanical stress and genotoxic drugs, whilst increased Dsg3 expression resulted in the opposite effects. Such a pathway in the negative regulation of p53 by Dsg3 was Dsg3 specific since neither E-cadherin nor desmoplakin knockdown caused similar effects. Analysis of Dsg3−/− mouse skin also indicated an increase of p53/p21WAF1/CIP1 and cleaved caspase-3 relative to Dsg3+/− controls. Finally, we evaluated whether this pathway was operational in the autoimmune disease PV in which Dsg3 serves as a major antigen involved in blistering pathogenesis. We uncovered increased p53 with diffuse cytoplasmic and/or nuclear staining in the oral mucosa of patients, including cells surrounding blisters and the pre-lesional regions. This finding was verified by in vitro studies where treatment of keratinocytes with PV sera, as well as a characterized pathogenic antibody specifically targeting Dsg3, evoked pronounced p53 expression and activity accompanied by disruption of cell–cell adhesion. Collectively, our findings suggest a novel role for Dsg3 as an anti-stress protein, via suppression of p53 function, and this pathway is disrupted in PV.
Highlights
Desmoglein-3 (Dsg3), a cadherin superfamily member, is an adhesion protein in desmosomes
Dsg[3] silencing caused their enhanced expression [premature cell differentiation] whereas the inverse result was detected in Dsg[3] overexpressing cells. These results suggest that the Dsg3-p53 pathway has some influence, at least in part, on the keratinocyte differentiation program
The data are expressed as the band intensities in the Dsg3-depleted cells relative to the corresponding scrambled siRNA controls, which were normalized to 1 total p53/phospho-p53-S20 (Fig. 3g, h) and this was marked in the case of SB203580 (Fig. 3h right panel). These findings suggest that, in the presence of DNA damage, Dsg[3] depletion further potentiates DNA double-strand breaks, which are involved in activation of ATM and its downstream targets CHK2 and p53, leading to cell cycle arrest and pre-apoptosis
Summary
Desmoglein-3 (Dsg3), a cadherin superfamily member, is an adhesion protein in desmosomes. Increased p53/p21WAF1/CIP1 was evident in the nuclear fraction of RNAi treated cells relative to control (Fig. 1c), confirming augmented p53 levels in cells with Dsg[3] depletion.
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