Meeting report – Desmosome dysfunction and disease: Alpine desmosome disease meeting

Abstract

Desmosome diseases are caused by dysfunction of desmosomes, which anchor intermediate filaments (IFs) at sites of cell–cell adhesion. For many decades, the focus of attention has been on the role of actin filament-associated adherens junctions in development and disease, especially cancer. However, interference with the function of desmosomes, their molecular constituents or their attachments to IFs has now emerged as a major contributor to a variety of diseases affecting different tissues and organs including skin, heart and the digestive tract. The first Alpine desmosome disease meeting (ADDM) held in Grainau, Germany, in October 2022 brought together international researchers from the basic sciences with clinical experts from diverse fields to share and discuss their ideas and concepts on desmosome function and dysfunction in the different cell types involved in desmosome diseases. Besides the prototypic desmosomal diseases pemphigus and arrhythmogenic cardiomyopathy, the role of desmosome dysfunction in inflammatory bowel diseases and eosinophilic esophagitis was discussed.

cAMP: A master regulator of cadherin‐mediated binding in endothelium, epithelium and myocardium

“…224,225 Interestingly, signaling traits regulating cell adhesion are shared in different desmosome-related diseases. 14 Since signaling by p38MAPK and EGFR have been found to be upregulated in models of both pemphigus and arrhythmogenic cardiomyopathy and ADAM17 was found to regulate desmosomal adhesion in keratinocytes in pemphigus and also in cardiomyocytes, 214,[242][243][244] it is possible that cAMP signaling may also serve as a possible target in other desmosome-related diseases. In addition, cAMP signaling may be employed to regulate the behavior of other cells.…”

“…Later, cAMP in the endothelium was found to regulate the Rho family GTPases and to control VE‐cadherin‐mediated adhesion, which was identified as a central barrier‐supporting adhesion molecule 12,13 . Since Rho family GTPases were identified to regulate cadherin adhesion in desmosomes, the role of cAMP to regulate desmosomal adhesion was explored in keratinocytes and in cardiomyocytes because these cell types are affected by the desmosome‐related diseases pemphigus and arrhythmogenic cardiomyopathy, respectively 14 . This review summarizes the current knowledge on the regulation of cadherin‐mediated adhesion by cAMP in different tissues and highlights components of the cAMP signaling cascade and its downstream molecules as targets for therapeutic approaches in disease.…”

“…12,13 Since Rho family GTPases were identified to regulate cadherin adhesion in desmosomes, the role of cAMP to regulate desmosomal adhesion was explored in keratinocytes and in cardiomyocytes because these cell types are affected by the desmosome-related diseases pemphigus and arrhythmogenic cardiomyopathy, respectively. 14 This review summarizes the current knowledge on the regulation of cadherin-mediated adhesion by cAMP in different tissues and highlights components of the cAMP signaling cascade and its downstream molecules as targets for therapeutic approaches in disease. 2 | cAMP SIGNALING PATHWAY cAMP was identified as a second messenger by Sutherland and Tall in 1958 15 and plays a critical role in a plethora of cellular functions such as the response to hormones and neurotransmitters, migration, mitochondrial homeostasis, proliferation and cell death.…”

Dsg3 epitope-specific signalling in pemphigus

“…Pemphigus is an autoantibody driven disease that impairs barrier integrity by disturbing the turnover of desmosomes. Desmosomes provide mechanical cohesion between neighbouring epithelial cells ( 1 ). As a result, liquid-filled blisters are formed within the epithelia, which can affect a large portion of the skin or mucous membranes.…”

Catalytic antibodies in arrhythmogenic cardiomyopathy patients cleave desmoglein 2 and N-cadherin and impair cardiomyocyte cohesion

“…Thus, AC pathogenesis may have aspects similar to pemphigus vulgaris (PV) -an autoimmune blistering skin disease caused by autoantibodies against DSG 3 [16][17][18] . This is of particular interest since both the structure of the ICD and the mechanisms regulating intercellular adhesion in cardiomyocytes share similarities to desmosomes in keratinocytes [19][20][21] .…”