Desmosomes: Essential contributors to an integrated intercellular junction network

Abstract

The development of adhesive connections between cells was critical for the evolution of multicellularity and for organizing cells into complex organs with discrete compartments. Four types of intercellular junction are present in vertebrates: desmosomes, adherens junctions, tight junctions, and gap junctions. All are essential for the development of the embryonic layers and organs as well as adult tissue homeostasis. While each junction type is defined as a distinct entity, it is now clear that they cooperate physically and functionally to create a robust and functionally diverse system. During evolution, desmosomes first appeared in vertebrates as highly specialized regions at the plasma membrane that couple the intermediate filament cytoskeleton at points of strong cell-cell adhesion. Here, we review how desmosomes conferred new mechanical and signaling properties to vertebrate cells and tissues through their interactions with the existing junctional and cytoskeletal network.

Keywords: Adherens junctions; Cadherins; Connexins; Cytoskeleton; Gap Junctions; Intermediate Filaments; Tight junctions.

Figure 1.. Organization of cell–cell junctions in different cell types.

A) In simple epithelia, the junctional complex comprises apical tight junctions followed by adherens junctions and their attached cortical actin ring, and then desmosomes, which anchor the intermediate filament network. Gap junctions on the lateral membrane mediate the transfer of small molecules from cell to cell. Cell-matrix adhesion is facilitated by hemidesmosomes and integrin-based focal adhesions. B) In cardiac myocytes, contractile units called sarcomeres comprising thick (myosin) and thin (actin) filaments are joined at Z-discs and stabilized by interwoven desmin intermediate filaments. Actin fibers and intermediate filaments are anchored at hybrid junctions called area composita containing desmosome and adherens junction components. Stand-alone desmosomes anchor the remaining desmin-intermediate filament, and connexin (Cx)-containing gap junctions facilitate synchronous beating in heart tissue. C) Schematic of the epidermis and its multiple layers including the basal proliferating layer and differentiating spinous layer, granular layer, and fully differentiated cornified layer. Junctional proteins are polarized across multiple layers, as reported in – . The patterns of junctional proteins and their attached cytoskeletons help drive the differentiation process. cad, cadherin; Cldn, claudin; CX, connexin; Dsc, desmocollin; Dsg, desmoglein; Jam-A, junctional adhesion molecule A; K, keratin; Ocln, occludin; Pkp, plakophilin; SG, stratum granulosum; Vinc, vinculin; ZO-1, zonula occludens 1.

Figure 2.. Schematics representing each of the major cell–cell junctions in simple epithelia and their major molecular components.

Adherens junctions anchor the actin cytoskeleton at points of cell–cell adhesion, mediated by homophilic interactions between the classical cadherins (Module 1). The armadillo protein β-catenin (Module 2) and actin-binding protein α-catenin (Module 3) connect cadherins to the actin cytoskeleton. Similarly, in desmosomes, adhesion is mediated through desmosomal cadherins, desmogleins (Dsg) and desmocollins (Dsc) (Module 1), which associate with armadillo proteins plakoglobin (Pg) and plakophilins (Pkp) (Module 2) and desmoplakin (DP) (Module 3) to anchor keratin-containing intermediate filaments to the membrane. In tight junctions, claudins and occludin are tetraspan membrane proteins that help form the paracellular barrier, and junctional adhesion molecules (JAM-A) assist in their assembly. Zonula occludens (ZO) proteins fortify the junction from the cytosolic side. Gap junctions are built from homo- or hetero-hexamers of connexin proteins to form a dodecamer connexin channel complex. These channels allow the flow of ions, small molecules, and proteins between cells. cAMP, cyclic adenosine monophosphate; cad, cadherin; DM, dense midline; ICS, intercellular space; IDP, inner dense plaque; IP ₃, inositol trisphosphate; ODP, outer dense plaque.

Figure 3.. Structural and functional interactions between cell–cell junctions.

Different components of cell–cell junctions work together to perform cellular processes and coordinate signaling events. From the perspective of the desmosome (DSM) (blue), here we list structural and/or functional relationships with tight junction (TJ) (yellow), adherens junction (AJ) (red), and gap junction (GJ) (green) components. Red and green arrows represent inhibition or activation, respectively, of DSM components. Black lines connecting DSM proteins with other junction components illustrate associations that promote or perturb junction form and function. The functional outcomes of these interactions are described over the connectors. Interactions represented in this figure are limited to those reported from 2014–2019. *Note: Sumigray et al. also reported a marked overexpression of claudins in desmoplakin (DP)-null keratinocytes. cad, cadherin; Cldns, claudins; CX43, connexin 43; Dsg, desmoglein; Occln, occludin; Pkp, plakophilin; ZO-1, zonula occludens 1.