Desmosome Assembly and Disassembly Are Membrane Raft-Dependent

Abstract

Strong intercellular adhesion is critical for tissues that experience mechanical stress, such as the skin and heart. Desmosomes provide adhesive strength to tissues by anchoring desmosomal cadherins of neighboring cells to the intermediate filament cytoskeleton. Alterations in assembly and disassembly compromise desmosome function and may contribute to human diseases, such as the autoimmune skin blistering disease pemphigus vulgaris (PV). We previously demonstrated that PV auto-antibodies directed against the desmosomal cadherin desmoglein 3 (Dsg3) cause loss of adhesion by triggering membrane raft-mediated Dsg3 endocytosis. We hypothesized that raft membrane microdomains play a broader role in desmosome homeostasis by regulating the dynamics of desmosome assembly and disassembly. In human keratinocytes, Dsg3 is raft associated as determined by biochemical and super resolution immunofluorescence microscopy methods. Cholesterol depletion, which disrupts rafts, prevented desmosome assembly and adhesion, thus functionally linking rafts to desmosome formation. Interestingly, Dsg3 did not associate with rafts in cells lacking desmosomal proteins. Additionally, PV IgG-induced desmosome disassembly occurred by redistribution of Dsg3 into raft-containing endocytic membrane domains, resulting in cholesterol-dependent loss of adhesion. These findings demonstrate that membrane rafts are required for desmosome assembly and disassembly dynamics, suggesting therapeutic potential for raft targeting agents in desmosomal diseases such as PV.

Palmitoylation of plakophilin is required for desmosome assembly

“…Recent studies have demonstrated that desmosomal components are associated with lipid rafts. (Brennan et al, 2012;Resnik et al, 2011;Stahley et al, 2014). Here, we have shown that plakophilin mutants that are unable to become palmitoylated show decreased association with lipid raft markers in sucrose-gradient centrifugation.…”

“…7). Recent studies have demonstrated that lipid raft association is required for desmosome assembly (Brennan et al, 2012;Resnik et al, 2011;Stahley et al, 2014). Palmitoylation is likely to influence the association of desmosomal components with this highly ordered membrane microdomain and thereby affect desmosome assembly.…”

“…Recent studies have demonstrated that desmosomal components are indeed associated with membrane microdomains enriched in lipid rafts components (Brennan et al, 2012;Resnik et al, 2011), and the disruption of lipid rafts has effects on desmosome dynamics (Stahley et al, 2014). We examined the ability of Myc-tagged wild-type plakophilins and plakophilin mutants to associate with lipid raft components by sucrose-gradient centrifugation.…”

Adducin Is Required for Desmosomal Cohesion in Keratinocytes

“…The latter is supported by the recent finding that the assembly of desmosomes but not of adherens junctions is lipid raft-dependent (47). Further work is not only required to elucidate these aspects but also needs to investigate whether adducin regulation is restricted to Dsg3 or affects other desmosmal adhesion molecules as well.…”

Insights into Desmosome Biology from Inherited Human Skin Disease and Cardiocutaneous Syndromes

“…Some of these factors are PKC, proteolytic processing through proteins such as ADAMs and cathepsins/cystatins, EGFR signalling, raft regulation and the yet unclear mechanism of the ubiquitin-proteasome system (UPS; Nekrasova & Green, 2013;Yin et al, 2005;Stahley et al, 2014;Loffek et al, 2012).…”