Desmosomal Cadherins and Signaling: Lessons from Autoimmune Disease

Abstract

Autoantibodies from patients suffering from the autoimmune blistering skin disease pemphigus can be applied as tools to study desmosomal adhesion. These autoantibodies targeting the desmosomal cadherins desmoglein (Dsg) 1 and Dsg3 cause disruption of desmosomes and loss of intercellular cohesion. Although pemphigus autoantibodies were initially proposed to sterically hinder desmosomes, many groups have shown that they activate signaling pathways which cause disruption of desmosomes and loss of intercellular cohesion by uncoupling the desmosomal plaque from the intermediate fi lament cytoskeleton and/or by interfering with desmosome turnover. These studies demonstrate that desmogleins serve as receptor molecules to transmit outside-in signaling and demonstrate that desmosomal cadherins have functions in addition to their adhesive properties. Two central molecules regulating cytoskeletal anchorage and desmosome turnover are p38MAPK and PKC. As cytoskeletal uncoupling in turn enhances Dsg3 depletion from desmosomes, both mechanisms reinforce one another in a vicious cycle that compromise the integrity and number of desmosomes.

Management of oral pemphigus vulgaris: A case report and a clinical update

“…Desmoglein 3, a 130 Kda component of desmosome, is the target antigen in this disease. 6,7 The most important aspect of PV is its early recognition, diagnosis, and treatment. 11 Dermatological examination is mandatory for all PV patients to evaluate the presence of skin or mucous lesions.…”

“…6 Although the exact mechanism is unclear, autoantibodies theoretically produce an allosteric change in the desmoglein, impairing its adhesive abilities, and increase active plasmin in the area, producing cell degradation and acantholysis. 6,7 Complement may be actively involved in this process. 7 Characteristically, PV lesions usually start affecting the oral mucosa, followed by the appearance of skin lesions months later.…”

“…6,7 Complement may be actively involved in this process. 7 Characteristically, PV lesions usually start affecting the oral mucosa, followed by the appearance of skin lesions months later. Most patients are initially misdiagnosed and improperly treated for many months or even years.…”

Desmosome assembly, homeostasis, and desmosomal disease

“…The first hypothesis proposes that anti-Dsg3 antibody interferes with intercellular adhesive function(s) of Dsg3 either by steric hindrance or by outside-in signaling, leading directly to desmosomal dissociation. 143 The second hypothesis proposes that several PV-IgG-induced intracellular signaling events could lead to desmosomal dissociation via intracellular and inside-out pathways. [144][145][146] Research suggests that PV-IgG does not directly inhibit desmosome formation, even though antibodies in PV-IgG may also cause steric hindrance between homophilic Dsg3 interactions and heterophilic Dsc3 interactions.…”

150thAnniversary Series: Desmosomes and Autoimmune Disease, Perspective of Dynamic Desmosome Remodeling and Its Impairments in Pemphigus

“…Especially, it is worthwhile to note that an anti-Dsg3 antibody, AK23, activates EGFR followed by an increase in Myc levels, events leading keratinocytes to proliferate in association with Dsg3 depletion and acantholysis in AK23-injected mice (Schulze et a., 2012). In addition, PKC involvement in pemphigus appears to be now well accepted in terms of generation of weak-adhesive desmosome condition (Cirillo et al, 2010;Kitajima, 2013;Spindler & Waschke, 2014). Furthermore, it has been shown that apoptosis signaling may be involved in pemphigus pathogenesis (Pelacho et al, 2004;Puviani et al, 2003;Wang et al, 2004).…”