Desmosomal Cadherins in Health and Disease

Abstract

Desmosomal cadherins are a recent evolutionary innovation that make up the adhesive core of highly specialized intercellular junctions called desmosomes. Desmosomal cadherins, which are grouped into desmogleins and desmocollins, are related to the classical cadherins, but their cytoplasmic domains are tailored for anchoring intermediate filaments instead of actin to sites of cell–cell adhesion. The resulting junctions are critical for resisting mechanical stress in tissues such as the skin and heart. Desmosomal cadherins also act as signaling hubs that promote differentiation and facilitate morphogenesis, creating more complex and effective tissue barriers in vertebrate tissues. Interference with desmosomal cadherin adhesive and supra-adhesive functions leads to a variety of autoimmune, hereditary, toxin-mediated, and malignant diseases. We review our current understanding of how desmosomal cadherins contribute to human health and disease, highlight gaps in our knowledge about their regulation and function, and introduce promising new directions toward combatting desmosome-related diseases. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 17 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Stabilization of Keratinocyte Monolayer Integrity in the Presence of Anti-Desmoglein-3 Antibodies through FcRn Blockade with Efgartigimod: Novel Treatment Paradigm for Pemphigus?

“…Desmosomes contain transmembrane proteins of the cadherin family, the desmogleins (Dsg) and desmocollins (Dsc), that mediate the intercellular adhesion by interacting with their counterparts on the surface of their neighboring cells. The cytoplasmic domains of Dsg and Dsc form complexes with plaque proteins, including plakoglobin, plakophilin and desmoplakin, which mediate the interaction with the keratin filaments (for a review, see [1]).…”

The Desmosome-Keratin Scaffold Integrates ErbB Family and Mechanical Signaling to Polarize Epidermal Structure and Function

“…In both cases, their proper distribution is necessary to generate an effective barrier appropriate for the function of the associated organ ( Alizadeh et al, 2021 ; Muller et al, 2021 ). Furthermore, these intercellular junctions engage in bi-directional communication with ErbB family members: they contribute to localization and activities of ErbB family members, and in turn, ErbB family members regulate the assembly, integrity, and function of the junctions ( Chiasson-MacKenzie and McClatchey, 2018 ; Muller et al, 2021 ; Hegazy et al, 2022 ).…”

“…Desmosomes exhibit a modular organization that parallels actin-associated AJs. Each mediate intercellular adhesion through members of the cadherin family of adhesion molecules and anchor their respective cytoskeletons through a complex of armadillo proteins and specific cytoskeletal adaptors ( Figure 1 ) ( Hegazy et al, 2022 ; Muller et al, 2021 ; Najor, 2018 ). Desmosomes stand apart, however, by being built from members of two cadherin subclasses, desmogleins (Dsgs) and desmocollins (Dscs).…”

“…Simple epithelial desmosomes have one each of these cadherins, Dsg2 and Dsc2, associated with the K8/18 keratin pair. Complex terrestrial tissues like the epidermis have seven different desmosomal cadherin genes expressed in differentiation-dependent, and in some cases reciprocal, gradient patterns ( Hegazy et al, 2022 ) ( Figure 2 ). Why desmosomes have two subclasses of cadherins is not fully understood, but it is notable that the tails of the Dsgs are longer than those of Dscs or of their classical cadherin counterparts, enabling association with several binding partners that mediate multiple specialized functions.…”

“…An important step in creating complex tissues was the appearance of desmosomes, which anchor the IF cytoskeleton to sites of strong cell-cell adhesion and are increasingly appreciated as integrators of chemical and mechanical signaling ( Najor, 2018 ; Muller et al, 2021 ; Hegazy et al, 2022 ). These connections arose in primitive form in jawless fish, reaching their highest complexity in terrestrial vertebrates ( Green et al, 2020 ), and are physically and functionally integrated with the actin-cadherin network in vertebrates ( Rubsam et al, 2018 ; Broussard et al, 2021 ; Prechova et al, 2022 ).…”