Desmosomes are intercellular junctions that connect intermediate filaments to the cell surface and mediate strong cell-cell adhesion. They are particularly prominent in stratified squamous epithelia and the myocardium, tissues that are normally subjected to significant mechanical stress. Desmosomes are dynamic structures whose functions extend beyond adhesive interactions. Recent comprehensive reviews have highlighted the structural and functional properties of desmosomal proteins and the mechanisms of desmosome regulation revealed by cell biological and biochemical approaches. In this Commentary, we examine various human disorders in which desmosomal components are affected by mutations or autoimmune responses, and identify underlying principles of desmosome biology that these diseases reveal.
Desmosomes are molecular complexes of cell adhesion proteins and linking proteins that attach the cell surface adhesion proteins to intracellular keratin cytoskeletal filaments. The cell adhesion proteins of the desmosome, desmoglein and desmocollin, are members of the cadherin family of cell adhesion molecules. They are transmembrane proteins that bridge the space between adjacent epithelial cells by way of homophilic binding of their extracellular domains to other desmosomal cadherins on the adjacent cell. Both have five extracellular domains, and have calcium-binding vulvae. The extracellular domain of the desmosome is called the extracellular core domain (ECD) or the desmoglea, and is bisected by an electron-dense midline where the desmoglein and desmocollin proteins bind to each other. These proteins can bind in a W, S, or λ manner.
The desmosome is a specialized adhesive junction that interacts with the cytoskeleton and participates in crosstalk with gap and adherens junctions. Mutations in components of the desmosome underlie a variety of cutaneous disorders and arrhythmogenic cardiomyopathy, a disease that bridges the gap between inherited arrhythmia syndromes and heart muscle disorders. The early, “concealed” phase of arrhythmogenic cardiomyopathy is characterized by a propensity to ventricular arrhythmia and sudden cardiac death (SCD) in the setting of well-preserved morphology, histology, and ventricular function.
Several fundamental aspects of desmosome biology can be inferred from an examination of the clinical presentations of human diseases in which desmosome structure and function are altered. First, it is clear that the primary role of the desmosome is to resist mechanical stress. The two tissues subjected to routine and substantial mechanical forces are the heart and the skin. Invariably, mutations in, or autoantibodies directed at, desmosomal proteins lead to compromised cardiac or cutaneous function - and sometimes both. Second, different clinical presentations often arise when different desmosomal components are affected or even when different regions of the same molecule are mutated. By contrast, virtually identical clinical manifestations can result from mutations in different desmosomal components. Desmosomes may thus function as nodes where protein components participate in common functions, such as adhesion, but also engage in others, such as cytoskeletal organization, cell signaling, and tissue patterning. Last, the complex expression profiles of desmosomal genes are important for the differentiation program of tissues such as the epidermis. These observations suggest that individual members of each gene family have arisen to support specific aspects of the differentiation process. Below, we expand upon these themes by examining several autoimmune and inherited disorders affecting desmosome structure and function.