150th anniversary series: Desmosomes in physiology and disease

Abstract

Cell–cell adhesion is essential for life in multicellular organisms. One of the prominent adhesive structures acting as stabilizing element in tissues is the desmosome. In addition to providing cohesion strength to tissues subjected to high mechanical stress, it has been recently recognized that desmosomes are also essential for tissue morphogenesis and differentiation. The crucial role of the desmosome in cell physiology is mirrored by the large number of diseases occurring when the function of one or more of its constituents is impaired. Hence, major efforts have been made over the last 20 years to understand the mechanisms underlying the pathobiology of intercellular adhesion, with a hope of developing new diagnostic and therapeutic tools; this, in turn, has allowed gaining more insights into the basic science of desmosome structure and function. These concepts will be briefly presented here and developed in detail in the upcoming cell adhesion series “Desmosomes in physiology and disease”, launched on the occasion of the 150th anniversary of the discovery of the desmosome in 1864.

Keywords::

• apoptosis
• cell adhesion
• desmosome
• heart disease
• morphogenesis
• skin disease

Intercellular cohesion is important at all levels in the human body, but becomes an essential requirement in tissues subjected to mechanical stress, such as the epidermis. The epidermal stratified squamous epithelium is a complex structure consisting mainly of keratinocytes adherent to each other. Cohesion among keratinocytes is needed for preserving the tissue architecture and function. Epithelial integrity is in fact guaranteed by at least three types of junctional structures (Figure 1): 1. anchoring junctions, including desmosomes and adherens junctions, which work with each other to hold epithelial sheets together; 2. tight junctions (zonula occludens), that are mainly adapted to establish a diffusion barrier between the apical and basolateral side of polarized cells; 3. gap junctions, that couple cells by intercellular channels, thus allowing for the direct exchange of small molecules between cells.

Figure 1. Schematic representation of the cell–cell junctions with well-recognized adhesion properties, including (a) desmosome, (b) adherent junction and (c) tight junction.

Desmosomes have been undergoing extensive studies over the last 20 years. The understanding of the pathobiological mechanisms of various acquired autoimmune and infectious blistering diseases (Cirillo & Al-Jandan, 2013), along with the identification of mutations in many desmosomal constituents that cause skin, hair and heart defects in humans (Brooke et al., 2012), have focused the attention of many investigators on such an intriguing structure. Furthermore, it has now become clear that desmosomes are dynamic structures that also participate in tissue morphogenesis and differentiation (Getsios et al., 2004). These themes will be briefly presented here as a prologue of the journal series.

INTRODUCING THE DESMOSOME: WHERE DOES IT COME FROM AND WHERE IS IT GOING?

The first description of desmosomes was given by the Italian pathologist Giulio Bizzozero (1864) almost 150 years ago; he described that those structures as small dense nodules at the contact points between adjacent cells, subsequently named “nodes of Bizzozero”. In 1920, Josef Shaffer coined the term desmosome, from the Greek “desmos” – meaning “bond” and “soma” – meaning “body”. Later, electron microscopy allowed for characterizing these “spot welds” as pairs of electron-dense attachment plaques, one for each adjacent cell. In the 1970s, the development of procedures to isolate intact desmosomes from tissues (Skerrow & Matoltsy, 1974) led to the biochemical characterization of the major protein components of the desmosomes. Subsequently, generation of specific antibodies against such desmosomal proteins and their use in immunolocalization and immunoreactivity experiments led to important observations regarding the biological significance of desmosomes (Cowin et al., 1984), including the expression pattern of desmosomal components in various tissues. These studies have provided evidence that the highly insoluble desmosomal structures are abundant between the keratinocytes of the skin epidermis and its appendages, as well as the myocytes of the heart, but can also be found in some specialized cells of the meninges and lymph nodes (Bazzi & Christiano, 2007). In the last two decades, cDNA cloning techniques and the advances in cell and molecular biology have clarified the structure and deduced amino-acidic sequence of major desmosomal proteins. Further insight into the understanding of their function have come from the study of desmosome-targeting diseases. Recent studies have finally uncovered that desmosomes play crucial roles in tissues’ formation and organization. The following paragraphs will briefly discuss old and new concepts of desmosome research and its relevance to human disease.

DESMOSOMES: WHAT THEY DO AND HOW THEY DO IT?

Desmosomes provide strong adhesion between cells undergoing mechanical stress and integrate signalling pathways that control cell behaviour and tissue morphogenesis.

Ultra-structurally, desmosomes consist of an extracellular (EC) core domain of about 34 nm (Al-Amoudi et al., 2004) that often contains a mid-line between the plasma membranes of adjacent cells and the intracellular symmetrical electron-dense plaques, each of which can be further subdivided into an outer and an inner dense plaque. The outer dense plaques are attached to the inner surface of the plasma membrane and consist of the COOH-terminal domains of the desmosomal transmembrane adhesion molecules, primarily the desmogleins (Dsg) and desmocollins (Dsc), and plaque proteins such as periplakin (Ppk), envoplakin (Epk), plakoglobin (PG), p0071, plakophilins (Pkp) and the NH2-terminus of desmoplakin (DP) (Figure 2). Because desmosomes also link intracellularly to the keratin intermediate filament (KIF) cytoskeleton they form the adhesive bonds – the desmosome/intermediate filament complex (DIFC) – in a network that confers mechanical resistance to tissues.

Figure 2. Molecular constituents of the desmosome, their structure and binding partners. Genetic, infectious, autoimmune and neoplastic diseases targeting desmosomal proteins are reported in the lower part of the panel. EC, extracellular; Dsg, desmogleins; Dsc, desmocollins; PG, plakoglobin; DP, desmoplakin; Pkp, plakophilin; Epk, envoplakin; Ppk, periplakin; KIF, keratin intermediate filaments.

Desmosomal proteins are expressed in tissue-specific manner. For instance, Dsc2 and Dsg2 are present ubiquitously in all tissues that contain desmosomes (Nuber et al., 1995; Schafer et al., 1994) and can be found in simple epithelia, as well as in the heart myocardium and basal layer of complex epithelia (Koch et al., 1992). The expression of Dsc/Dsg3 and Dsc/Dsg1 is, in contrast, restricted to certain stratified, squamous epithelia. Within the epidermis, desmosomal proteins’ expression is regulated in a differentiation-specific pattern, that explains why changes in each of the desmosomal proteins may affect different layers of the epidermis (Figure 3).

Figure 3. Differentiation-specific distribution of the desmosomal proteins within the epidermis. Dsg, desmogleins; Dsc, desmocollins; PG, plakoglobin; DP, desmoplakin; Pkp, plakophilin.

The EC domains of the Dsg and Dsc are highly homologous to those of the Type I cadherin prototype, E-cadherin, which contains four similar cadherin repeats (EC1-4) each about 110 amino acids in length, containing a calcium-binding motif and one less-related membrane-proximal EC domain (EC5). Their high degree of adhesive strength is based on multiple and extremely strong non-covalent interactions between its EC constituents, that may be either Ca²⁺-independent, in desmosome's hyper-adhesive state, or Ca²⁺-dependent, when dynamic cell behaviour requiring cell–cell contact rearrangements is needed. The structural basis of this Ca²⁺-dependence are, however, still subject to dispute. Study by other groups based on the crystal structure of C-cadherin suggests that the EC domains to be curved (for review see Garrod & Chidgey, 2008). On the other hand, a cryo-electron microscopy study suggests that they are straight (Al-Amoudi et al., 2004). The curvature in the crystal structure permits both trans and cis interactions between the cadherin molecules and it has been speculated that the latter may be crucial in relation to calcium independence.

THE DESMOSOME IN CELL PHYSIOLOGY AND DISEASE

The crucial role of the desmosome in maintaining tissue integrity is demonstrated by the large number of diseases occurring when the function of one or more of its constituents is impaired (Figure 2). In turn, the study of disease pathophysiology has allowed to gain more insights into desmosome structure and function. Novel insights into the biochemistry and dynamic structure of the desmosome and how these findings may apply to human skin diseases will be illustrated by Yasuo Kitajima. A major contribution to the understanding of how desmosomes can change their adhesive status has been provided by David Garrod, who will present his new concept of desmosome hyper-adhesion. The dynamic process of desmosome assembly and disassembly has been also recognized to be fundamental for morphogenesis, a process where apoptosis plays a pathophisiologically relevant role. These themes will be dealt with in detail by Nicola Cirillo and Otmar Huber. Altered desmosomal function may also affect non-epidermal tissues such as the myocardium, as research published by Adalena Tsatsopoulou shows. Andrew South’s group will focus on the human disorders in which desmosomal components are affected by gene mutations. The review by Gerard Lina will report recent evidence on how infectious diseases, including Staphylococcal scalded skin syndrome, do develop when specific desmosomal proteins are cleaved. Finally, a role for desmosomes in cancer and metastasis has been emerging over the last few years and will be addressed by Huber's group, who made a major contribution in this field.

Declaration of interest: The author reports no declarations of interest. The author alone is responsible for the content and writing of the paper.