Plakoglobin Rescues Adhesive Defects Induced by Ectodomain Truncation of the Desmosomal Cadherin Desmoglein 1

Abstract

Desmoglein 1 (Dsg1) is a desmosomal cadherin that is essential to epidermal integrity. In the blistering diseases bullous impetigo and staphylococcal scaldedskin 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 (⌬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-dependent 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 rescues cadherin expression, desmosome organization, and functional adhesion in cells expressing ⌬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. Desmosomes are specialized intercellular adhesive organelles crucial for maintaining the integrity of tissues that endure mechanical stress, especially the epidermis. 1The adhesive interface of desmosomes is built from specialized cadherin family members, including four desmogleins (Dsg1-4) and three desmocollins (Dsc1-3), assembled at junctions between epidermal keratinocytes. Desmogleins and desmocollins cooperate to mediate adhesion with cadherins on neighboring cells via ectodo-

Desmoglein-1/Erbin interaction suppresses ERK activation to support epidermal differentiation

“…To begin addressing which DSG1 domains are important for Erbin binding, we tested several previously published DSG1 truncation mutants (10,48). These included an N-terminal truncation designed to mimic cleavage of DSG1 adhesive domains by bacterial toxins associated with bullous impetigo [Δ381(WT)] (14,48).…”

“…These included an N-terminal truncation designed to mimic cleavage of DSG1 adhesive domains by bacterial toxins associated with bullous impetigo [Δ381(WT)] (14,48). Truncated DSG1 retained an affinity for Erbin, as did a second construct combining the truncation with mutations engineered to disrupt DSG1-Pg interactions [Δ381(AAA)] (Figure 2, G and H).…”

Desmosomes: Regulators of Cellular Signaling and Adhesion in Epidermal Health and Disease

“…Epigenetic mechanisms, including promoter methylation and histone deacetylation (HDAC), also repress the expression of desmosomal proteins, which may contribute to carcinogenesis (Potter et al 2001;Cui et al 2011;Kaz et al 2012;Yang et al 2012). The consequent loss of desmosome-mediated adhesion can be restored in part by HDAC inhibitors (Shim et al 2004;Simpson et al 2010). Furthering our understanding of the transcriptional programs that regulate desmosomal pro- tein expression will be an important prerequisite for pharmacologically intervening in disorders involving these molecules.…”

“…Pg and Dsg2 expression reduces the blistering associated with attack by these toxins (Brennan et al 2010;Simpson et al 2010). Use of therapeutic agents that increase expression of desmosomal cadherins and Pg such as EGFR inhibitors, histone deacetylase inhibitors, or tyrosine phosphatase inhibitors like sodium pervanadate (Lorch et al 2004;Garrod et al 2008;Simpson et al 2010;Aktary and Pasdar 2012) may lessen the severity of blistering in pemphigus and Staphylococcal infections.…”

“…Other drugs that increase desmosomal protein expression and strengthen desmosomes may lead to reduced symptoms arising from desmosomal diseases, reduced epidermal damage after environmental exposure, and prevention of carcinogenesis. These include EGFR inhibitors, histone deacetylase inhibitors, cholinergic agonists, or tyrosine phosphatase inhibitors like sodium pervanadate (Nguyen et al 2003;Lorch et al 2004;Garrod et al 2008;Simpson et al 2010;Aktary and Pasdar 2012;Johnson et al 2014).…”