Pemphigus is a class of devastating epidermal blistering diseases in which autoantibodies are generated against cell-cell adhesion molecules present in the skin and mucous membranes. Pemphigus IgG target desmosomes, a structure that couples the keratin intermediate filament network to regions of strong cell-cell adhesion. In pemphigus vulgaris (PV), the primary target of the autoantibodies is desmoglein-3 (Dsg3), a member of the desmosomal cadherin subfamily of adhesion molecules. The work outlined in this application investigates the mechanisms by which IgG from pemphigus vulgaris patients disrupts cell-cell adhesion. It is hypothesized that PV IgG disrupt desmosomes by causing Dsg3 internalization from the cell surface, leading to desmosome destabilization and loss of keratinocyte adhesion. This hypothesis will be tested using a series of in vitro cell culture models that employ cellular and molecular approaches to define the mechanisms by which PV IgG cause Dsg3 internalization and desmosome disassembly. These studies will reveal the cellular machinery and pathways that mediate Dsg3 endocytosis, and how cytoplasmic components of the desmosome regulate Dsg3 internalization. Furthermore, a panel of antibody reagents will be employed, including PV patient IgG, human monoclonal antibodies cloned from patients, and mouse monoclonal Dsg3 antibodies with varying degrees of pathogenic activity. These reagents will be used to reveal relationships between desmosome disassembly pathways and antibody pathogenicity profiles to determine how pemphigus IgG causes disease at the cellular level.
These studies are designed to generate new insights into the basic cellular mechanisms that regulate cell-cell adhesion, and to expose new therapeutic targets for the treatment of pemphigus and other skin diseases characterized by epidermal fragility.
|Cadwell, Chantel M; Jenkins, Paul M; Bennett, Vann et al. (2016) Ankyrin-G Inhibits Endocytosis of Cadherin Dimers. J Biol Chem 291:691-704|
|Roberts, Brett J; Svoboda, Robert A; Overmiller, Andrew M et al. (2016) Palmitoylation of Desmoglein 2 Is a Regulator of Assembly Dynamics and Protein Turnover. J Biol Chem 291:24857-24865|
|Stahley, Sara N; Bartle, Emily I; Atkinson, Claire E et al. (2016) Molecular organization of the desmosome as revealed by direct stochastic optical reconstruction microscopy. J Cell Sci 129:2897-904|
|Stahley, Sara N; Warren, Maxine F; Feldman, Ron J et al. (2016) Super-Resolution Microscopy Reveals Altered Desmosomal Protein Organization in Tissue from Patients with Pemphigus Vulgaris. J Invest Dermatol 136:59-66|
|Stahley, Sara N; Warren, Maxine F; Feldman, Ron J et al. (2015) Super-Resolution Microscopy Reveals Altered Desmosomal Protein Organization in Pemphigus Vulgaris Patient Tissue. J Invest Dermatol :|
|Stahley, Sara N; Kowalczyk, Andrew P (2015) Desmosomes in acquired disease. Cell Tissue Res 360:439-56|
|Stahley, Sara N; Saito, Masataka; Faundez, Victor et al. (2014) Desmosome assembly and disassembly are membrane raft-dependent. PLoS One 9:e87809|
|Tucker, Dana K; Stahley, Sara N; Kowalczyk, Andrew P (2014) Plakophilin-1 protects keratinocytes from pemphigus vulgaris IgG by forming calcium-independent desmosomes. J Invest Dermatol 134:1033-43|
|Kowalczyk, Andrew P; Green, Kathleen J (2013) Structure, function, and regulation of desmosomes. Prog Mol Biol Transl Sci 116:95-118|
|Kowalczyk, Andrew P; Nanes, Benjamin A (2012) Adherens junction turnover: regulating adhesion through cadherin endocytosis, degradation, and recycling. Subcell Biochem 60:197-222|
Showing the most recent 10 out of 29 publications