title: Plakoglobin rescues adhesive defects induced by ectodomain truncation of the desmosomal cadherin desmoglein 1: implications for exfoliative toxin-mediated skin blistering.
abstract: Desmoglein 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 (Δ381-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 Δ381-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.
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, 303 E. Chicago Ave., Chicago, IL 60611, USA.
authors.forename: Cory L
authors.initials: CL
authors.lastname: Simpson
authors.forename: Shin-ichiro
authors.initials: S
authors.lastname: Kojima
authors.forename: Victoria
authors.initials: V
authors.lastname: Cooper-Whitehair
authors.forename: Spiro
authors.initials: S
authors.lastname: Getsios
authors.forename: Kathleen J
authors.initials: KJ
authors.lastname: Green
mesh_terms: D001768:Blister / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D002448:Cell Adhesion / Q000235:genetics; D002478:Cells, Cultured; D003873:Dermatitis, Exfoliative / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D051183:Desmoglein 1 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D051181:Desmosomal Cadherins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D005083:Exfoliatins / Q000009:adverse effects* / Q000494:pharmacology; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D054730:Protein Interaction Domains and Motifs / Q000235:genetics* / Q000502:physiology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017384:Sequence Deletion / Q000502:physiology*; D012867:Skin / Q000378:metabolism / Q000473:pathology; D013207:Staphylococcal Skin Infections / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014161:Transduction, Genetic; D051185:gamma Catenin / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: C495297:DSG1 protein, human; D051183:Desmoglein 1; D051181:Desmosomal Cadherins; D005083:Exfoliatins; D051185:gamma Catenin