Patients with the blistering disease pemphigus foliaceus (PF) have circulating autoantibodies whose antigenic target is a transmembrane desmosomal cadherin called desmoglein 1 (Dsg1). It has been hypothesized that PF IgG might directly inhibit cell adhesion by binding to the extracellular domain of Dsg1 antibodies directly cause PF blisters, nor had Dsg1's role in adhesion been investigated. Over the last funding period substantial progress has been made to define specific epitopes against which PF antibodies are directed, to determine that binding of PF antibodies to these epitopes is dependent on their correct conformation and to demonstrate that anti-Dsg1 antibodies are pathogenic in the disease. However, the precise mechanism by which anti-Dsg1 results in acantholysis is not known. Elucidating this process will depend on first understanding how the desmosomal cadherin adhesive complex is assembled, maintained and regulated.
Our aims for the next five years are: 1. To define the contribution of Dsg1 and other desmosomal cadherins to cell-cell adhesion in a fibroblast reconstitution system and to test the hypothesis that the cytoskeletal linker, desmoplakin, is required for desmosomal cadherin-mediated adhesion. 2. To establish the organization of the desmosomal cadherin extracellular domains at the adhesive interface of desmosomes by cross-linking keratinocyte cell surface molecules and analyzing cross-links by peptide sequencing. 3. To investigate the basis and biological significance of the unusual 6:1 stoichiometry exhibited by the plakoglobin:Dsg1 complex and whether plakoglobin:Dsg1 interactions are regulated by phosphorylation of the Dsg1 cytoplasmic tail, and 4. To examine the consequences of ectopically expressing Dsg1 or dominant negative plakoglobin mutants on adhesion, stratification and keratinocyte differention in organotypic raft cultures.
|Yang, Ruiguo; Broussard, Joshua A; Green, Kathleen J et al. (2018) Techniques to stimulate and interrogate cell-cell adhesion mechanics. Extreme Mech Lett 20:125-139|
|Vodo, D; O'Toole, E A; Malchin, N et al. (2018) Striate palmoplantar keratoderma resulting from a missense mutation in DSG1. Br J Dermatol 179:755-757|
|Polivka, Laura; Hadj-Rabia, Smail; Bal, Elodie et al. (2018) Epithelial barrier dysfunction in desmoglein-1 deficiency. J Allergy Clin Immunol 142:702-706.e7|
|Nekrasova, Oxana; Harmon, Robert M; Broussard, Joshua A et al. (2018) Desmosomal cadherin association with Tctex-1 and cortactin-Arp2/3 drives perijunctional actin polymerization to promote keratinocyte delamination. Nat Commun 9:1053|
|Mohamad, Janan; Sarig, Ofer; Godsel, Lisa M et al. (2018) Filaggrin 2 Deficiency Results in Abnormal Cell-Cell Adhesion in the Cornified Cell Layers and Causes Peeling Skin Syndrome Type A. J Invest Dermatol 138:1736-1743|
|Rübsam, Matthias; Broussard, Joshua A; Wickström, Sara A et al. (2018) Adherens Junctions and Desmosomes Coordinate Mechanics and Signaling to Orchestrate Tissue Morphogenesis and Function: An Evolutionary Perspective. Cold Spring Harb Perspect Biol 10:|
|Broussard, Joshua A; Yang, Ruiguo; Huang, Changjin et al. (2017) The desmoplakin-intermediate filament linkage regulates cell mechanics. Mol Biol Cell 28:3156-3164|
|Samuelov, Liat; Li, Qiaoli; Bochner, Ron et al. (2017) SVEP1 plays a crucial role in epidermal differentiation. Exp Dermatol 26:423-430|
|Jones, Jonathan C R; Kam, Chen Yuan; Harmon, Robert M et al. (2017) Intermediate Filaments and the Plasma Membrane. Cold Spring Harb Perspect Biol 9:|
|Broussard, Joshua A; Green, Kathleen J (2017) Research Techniques Made Simple: Methodology and Applications of Förster Resonance Energy Transfer (FRET) Microscopy. J Invest Dermatol 137:e185-e191|
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