Plakoglobin Rescues Adhesive Defects Induced by Ectodomain Truncation of the Desmosomal Cadherin Desmoglein 1 Implications for Exfoliative Toxin-Mediated Skin Blistering

Desmoglem 1 (Dsg1) is a desmosomal cadherin that is essential to epidermal integrity In the blistering diseases bullous impetigo and staphylococcal scalded skin syndrome pathogenesis depends on cleavage of Dsg1 by a bacterial protease exfoliative toxin A which removes residues 1 to 381 of the Dsg1 ectodomain However the cellular responses to Dsg1 cleavage that precipitate keratinocyte separation to induce blister formation are unknown Here we show that ectodomain deleted Dsg1 (Delta 381 Dsg1) mimics the toxin cleaved cadherin disrupts desmosomes and reduces the mechanical integrity of keratinocyte sheets In addition we demonstrate that truncated Dsg1 remains associated with its catenin partner plakoglobin and causes a reduction in the levels of endogenous desmosomal cadherins in a dose de pendent manner leading us to hypothesize that plakoglobin sequestration by truncated Dsg1 destabilizes other cadherins Accordingly a triple point mutant of the ectodomain deleted cadherin which is uncoupled from plakoglobin does not impair adhesion indicating that this interaction is essential to the pathogenic potential of truncated Dsg1 Moreover we demonstrate that increasing plakoglobin levels res cues cadherin expression desmosome organization and functional adhesion m cells expressing Delta 381 Dsg1 or treated with exfoliative toxin A Finally we report that histone deacetylase Inhibition up regulates desmosomal cadherins and prevents the loss of adhesion induced by Dsg1 truncation These findings further our understanding of the mechanism of exfoliative toxin induced pathology and suggest novel strategies to suppress blistering in bulbous impetigo and staphylococcal scalded skin syndrome (Am J Pathol 2010 177 2921-2937 DOI 10 2353/ajpath 2010 100397)