MINIREVIEW
Desmogleins as signaling hubs regulating cell cohesion and tissue/organ function in skin and heart — EFEM lecture 2018

https://doi.org/10.1016/j.aanat.2018.11.006Get rights and content

Abstract

Cell–cell contacts are crucial for intercellular cohesion and formation of endothelial and epithelial barriers. Desmosomes are the adhesive contacts providing mechanical strength to epithelial intercellular adhesion and therefore are most abundant in tissues subjected to high mechanical stress such as the epidermis and heart muscle. Desmogleins (Dsg) besides intercellular adhesion serve as signalling hubs regulating cell behaviour. In desmosomal diseases such as the autoimmune blistering skin disease pemphigus or arrhythmic cardiomyopathy (AC), which is caused by mutations of desmosomal components of cardiomyocyte intercalated discs, the adhesive and signalling functions of desmosomes are impaired. Therefore, our goal is to elucidate the mechanisms regulating adhesion of desmosomes in order to develop new strategies to treat desmosomal diseases. For pemphigus, we have provided evidence that intracellular signalling is required for loss of keratinocyte cohesion and have characterized a first disease-relevant adhesion receptor consisting of Dsg3 and p38MAPK. We propose that signalling patterns correlate with autoantibody profiles and thereby define the clinical phenotypes of pemphigus. Besides direct modulation of signalling pathways we have demonstrated that peptide-mediated crosslinking of Dsg molecules can abolish skin blistering in vivo. A similar approach may be effective to stabilize adhesion in cardiomyocytes of AC hearts. Since we observed that the adrenergic β1-receptor is localized at intercalated discs we evaluate signalling pathways regulating cardiomyocyte cohesion. With adrenergic signalling we have reported a first mechanism to stabilize desmosomal adhesion in intercalated discs and proposed a new function of the sympathicus in the heart we refer to as positive adhesiotropy.

Introduction

Desmosomes besides adherens junctions, are the adhesive contacts providing mechanical coupling of neighboring cells and have been shown to regulate tissue morphogenesis and function (Johnson et al., 2014, Rubsam et al., 2017, Waschke, 2008). The adhesion molecules of desmosomes belong to the cadherin super-family and are anchored to the intermediate filament cytoskeleton via adaptor proteins such as plakoglobin (Pg), plakophilin and desmoplakin. These adaptor proteins organize desmosomes by forming two electron-dense plaques underneath the cell membrane which render the unique ultrastructural appearance of a desmosome. In simple epithelia and cardiomyocytes Dsg2 and desmocollin (Dsc) 2 are expressed as a single pair of desmosomal cadherins. In contrast, in complex epithelia such as the epidermis four Dsg and three Dsc isoforms are expressed in layer-specific patterns.

There is still matter of debate whether desmosomal cadherins predominantly undergo homophilic or heterophilic binding (Vielmuth et al., 2018a). This can be tested by performing single-molecule atomic force microscopy (AFM) under cell-free conditions when interaction of recombinant Dsg isoforms is blocked by specific inhibitory antibodies. With this approach, in several studies we have observed Ca2+-dependent homophilic adhesion of Dsg1–3 and Dsc3 (Heupel et al., 2009, Heupel et al., 2008, Schlegel et al., 2010, Spindler et al., 2009, Spindler et al., 2015, Spindler et al., 2013, Ungewiss et al., 2018, Ungewiss et al., 2017, Vielmuth et al., 2015a, Vielmuth et al., 2015b, Vielmuth et al., 2018b, Vielmuth et al., 2018c, Walter et al., 2017, Waschke et al., 2005, Waschke et al., 2007) whereas heterophilic binding was detectable between Dsg1 and Dsc3 (Spindler et al., 2009) and Dsg2 and Dsg3 (Vielmuth et al., 2018c) only. Besides, the extracellular domain of Dsg2 can also interact directly with epidermal growth factor receptor (EGFR), which maybe relevant to shape the function of EGFR from cell proliferation towards cell adhesion (Ungewiss et al., 2018).

Desmosomal diseases are defined by dysfunction of desmosomes and comprise pemphigus and arrhythmic cardiomyopathy as the most-well entities (Waschke, 2008). Some people may wonder whether desmosomes are important since they do not exist in flies. However, as a physician I am convinced that desmosomal diseases are a good indication that we are not flies and demonstrate that desmosomes are of biomedical relevance. Desmosomal diseases are rare but severe. For example, most patients suffering from pemphigus until the sixties of last century, i.e. until systemic glucocorticoids became available, died within two years. Until today, therapy is limited to unspecific immunosuppression, which is accompanied with significant side-effects. Similarly, in arrhythmogenic cardiomyopathy (AC), young adults and primarily athletes die from sudden cardiac death due to malign arrhythmia. Therefore, our goal is to better characterize the adhesive and signalling functions of desmosomes and to elucidate the mechanisms regulating adhesion of desmosomes in order to develop new strategies to enhance desmosome function. In the long run, this may provide the basis for new therapeutic approaches to cure patients suffering from desmosomal diseases.

We also obtained data indicating that the desmosomal protein desmoglein 2 (Dsg2) may contribute to the intestinal epithelial barrier dysfunction in Crohn’s disease (Schlegel et al., 2010, Spindler et al., 2015, Ungewiss et al., 2018, Ungewiss et al., 2017), which is supported by very recent in vivo studies from another group (Gross et al., 2018). However, inflammatory bowel diseases are at present not regarded as desmosomal diseases because their pathogenesis is multifactorial. Therefore, this Mini-Review focuses on approaches to stabilize desmosomal adhesion in pemphigus and in AC.

Section snippets

In pemphigus, autoantibodies interfere with the adhesive and signaling function of desmosomes

Pemphigus is a model disease to study both mechanisms regulating the turn-over of desmosomes as well as the pathogenesis of desmosomal diseases. This is due the fact that skin blistering in pemphigus, which is mediated by intra-epidermal splitting, is caused primarily by antibodies against Dsg1 and Dsg3 whereas the significance of a plethora of other autoantibodies is unclear yet (Spindler et al., 2018). This is different to most other autoimmune diseases where autoantibodies are produced

Adrenergic signaling stabilizes cardiomyocyte cohesion which we refer to as positive adhesiotropy

AC is a rare heart disease manifesting mostly when young adults and primarily athletes die from sudden cardiac death resulting from arrhythmia. It is well-established that AC is caused primarily by mutations in genes coding the desmosomal components of the intercalated disc (Corrado et al., 2017). As outlined above, our goal is to characterize AC pathogenesis in order to establish new strategies for therapy. Therefore, we transfer the insights gained from regulation of desmosomal adhesion in

Acknowledgements

At the XXVI International Symposium of Morphological Sciences (ISMS) 2018, held in Prague from July 5–7, 2018, it was my huge honor and great pleasure to deliver the 11th lecture of the European Federation for Experimental Morphology (EFEM). The theme of the symposium was “From molecule to organ in the heart of Europe”. In this article, I outlined the main thoughts of the lecture. In all our projects we study the interplay between cell cohesion and signaling and have a strong medical focus on

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