Peptide-mediated desmoglein 3 crosslinking prevents pemphigus vulgaris autoantibody-induced skin blistering
Open Access
- 9 January 2013
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 123 (2), 800-811
- https://doi.org/10.1172/jci60139
Abstract
In pemphigus vulgaris, a life-threatening autoimmune skin disease, epidermal blisters are caused by autoantibodies primarily targeting desmosomal cadherins desmoglein 3 (DSG3) and DSG1, leading to loss of keratinocyte cohesion. Due to limited insights into disease pathogenesis, current therapy relies primarily on nonspecific long-term immunosuppression. Both direct inhibition of DSG transinteraction and altered intracellular signaling by p38 MAPK likely contribute to the loss of cell adhesion. Here, we applied a tandem peptide (TP) consisting of 2 connected peptide sequences targeting the DSG adhesive interface that was capable of blocking autoantibody-mediated direct interference of DSG3 transinteraction, as revealed by atomic force microscopy and optical trapping. Importantly, TP abrogated autoantibody-mediated skin blistering in mice and was effective when applied topically. Mechanistically, TP inhibited both autoantibody-induced p38 MAPK activation and its association with DSG3, abrogated p38 MAPK-induced keratin filament retraction, and promoted desmosomal DSG3 oligomerization. These data indicate that p38 MAPK links autoantibody-mediated inhibition of DSG3 binding to skin blistering. By limiting loss of DSG3 transinteraction, p38 MAPK activation, and keratin filament retraction, which are hallmarks of pemphigus pathogenesis, TP may serve as a promising treatment option.Keywords
This publication has 54 references indexed in Scilit:
- Desmoplakin Regulates Desmosome HyperadhesionJournal of Investigative Dermatology, 2012
- The Extent of Desmoglein 3 Depletion in Pemphigus Vulgaris Is Dependent on Ca2+-Induced DifferentiationThe American Journal of Pathology, 2011
- Linking of Sensor Molecules with Amino Groups to Amino-Functionalized AFM TipsBioconjugate Chemistry, 2011
- IgG Autoantibodies Against Desmocollin 3 in Pemphigus Sera Induce Loss of Keratinocyte AdhesionThe American Journal of Pathology, 2011
- p38MAPK Signaling and Desmoglein-3 Internalization Are Linked Events in Pemphigus AcantholysisJournal of Biological Chemistry, 2010
- Two-step adhesive binding by classical cadherinsNature Structural & Molecular Biology, 2010
- Desmocollin 3-mediated Binding Is Crucial for Keratinocyte Cohesion and Is Impaired in PemphigusPublished by Elsevier BV ,2009
- The desmosome and pemphigusHistochemistry and Cell Biology, 2008
- p38MAPK inhibition prevents disease in pemphigus vulgaris miceProceedings of the National Academy of Sciences of the United States of America, 2006
- Pemphigus vulgaris identifies plakoglobin as key suppressor of c-Myc in the skinThe EMBO Journal, 2006