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PMID: 21075858 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Plakoglobin rescues adhesive defects induced by ectodomain truncation of the desmosomal cadherin desmoglein 1: implications for exfoliative toxin-mediated skin blistering.

The American journal of pathology ·Vol. 177 ·No. 6 ·2010-12-00 ·Pages 2921-37

Simpson CL, Kojima S, Cooper-Whitehair V, Getsios S, Green KJ

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.

MeSH Terms
Blister/etiology,genetics,pathology Cell Adhesion/genetics Cells, Cultured Dermatitis, Exfoliative/etiology,genetics,pathology Desmoglein 1/chemistry,genetics,metabolism,physiology Desmosomal Cadherins/chemistry,genetics,metabolism,physiology Exfoliatins/adverse effects,pharmacology Humans Keratinocytes/drug effects,metabolism,pathology,physiology Protein Interaction Domains and Motifs/genetics,physiology Protein Processing, Post-Translational/drug effects Sequence Deletion/physiology Skin/metabolism,pathology Staphylococcal Skin Infections/genetics,metabolism,pathology Transduction, Genetic gamma Catenin/genetics,metabolism,physiology
Chemicals
DSG1 protein, human Desmoglein 1 Desmosomal Cadherins Exfoliatins gamma Catenin
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Simpson Cory L
Department of Pathology, Northwestern University Feinberg School of Medicine, 303 E. Chicago Ave., Chicago, IL 60611, USA.
Kojima Shin-ichiro
Cooper-Whitehair Victoria
Getsios Spiro
Green Kathleen J
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Article Info
Journal
The American journal of pathology
Abbr.
Am J Pathol
ISSN
1525-2191
DOI
10.2353/ajpath.2010.100397
Published
2010-12-00
Epub
2010-00-12
Pages
2921-37
Language
English
Region
United States
NLM ID
0370502
PMCID
PMC2993287
Subset
IM
Grants
NIAMS NIH HHS · P30 AR057216 · United States
NCI NIH HHS · R01-CA122151 · United States
NIEHS NIH HHS · F30-ES014990 · United States
NCI NIH HHS · P30-CA060553 · United States
NIEHS NIH HHS · F30 ES014990 · United States
NCI NIH HHS · P30 CA060553 · United States
NIAMS NIH HHS · R01-AR041836 · United States
NCI NIH HHS · R01 CA122151 · United States
NIAMS NIH HHS · R01 AR041836 · United States
NIAMS NIH HHS · P30-AR057216 · United States
Corrections
CommentIn
PMID: 21056996
External Links
PubMed source DOI: 10.2353/ajpath.2010.100397 PMC Full Text View journal details
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