Desmosomes: regulators of cellular signaling and adhesion in epidermal health and disease

Abstract

Desmosomes are intercellular junctions that mediate cell-cell adhesion and anchor the intermediate filament network to the plasma membrane, providing mechanical resilience to tissues such as the epidermis and heart. In addition to their critical roles in adhesion, desmosomal proteins are emerging as mediators of cell signaling important for proper cell and tissue functions. In this review we highlight what is known about desmosomal proteins regulating adhesion and signaling in healthy skin-in morphogenesis, differentiation and homeostasis, wound healing, and protection against environmental damage. We also discuss how human diseases that target desmosome molecules directly or interfere indirectly with these mechanical and signaling functions to contribute to pathogenesis.

Figure 1.

Desmosome structure and organization. Electron micrograph of a desmosome from bovine tongue epithelium overlaid with a representation of the membrane and plaque components. Desmosomes are composed of cadherins (Desmoglein, Dsg; Desmocollin, Dsc), armadillo proteins (Plakoglobin, Pg; Plakophilin, Pkp), and a plakin (Desmoplakin, Dp), which act as a cytolinker to tether the desmosome to the intermediate filaments (IF).

Figure 2.

Desmosome differential protein expression pattern in epidermis and the transcription factors linked to their regulation. Several of the desmosomal components display a unique spatial pattern of expression within the epidermis (depicted as triangles and rectangles). We have summarized the transcriptional regulation of the desmosomal components from multiple cell types in Table 1. Desmosomal regulators that have been verified in the epidermis (no asterisk) are distinguished from those verified in other tissues (asterisk). Transcription factors regulating Pkp1, Dsg3, and Dsg2 are putative or unknown.

Figure 3.

Signaling roles of the desmosome. The desmosome has been linked to signaling pathways that regulate biological mechanisms such as wound healing, proliferation, differentiation, and apoptosis. Here we summarize signaling mechanisms that promote epidermal differentiation and proper desmosome assembly or remodeling.

Figure 4.

Diseases associated with the desmosome. Many diseases causing epidermal and cardiac tissue impairment are linked to improper desmosome functioning. Highlighted here are three different diseases (Pemphigus, ARVC, and SPPK) that are caused by autoimmunity and genetic mutations. It is important to note that SPPK is also caused by mutations in the genes of Plakoglobin and Desmoplakin (JUP and DSP). We have summarized the molecular pathway of SPPK caused by mutations in DSG1, and show tissue staining from SPPK patients harboring mutant Dsg1 (p.S132X) (Harmon et al. 2013).