Desmosomes are microscopic rivets that bolt neighboring cells together, giving tissues the strength to hold up under pulling, stretching, and friction. Found most abundantly in skin and heart muscle, these tiny protein complexes anchor the internal skeleton of one cell to the internal skeleton of the next, creating a continuous network that distributes mechanical force across an entire tissue rather than letting it concentrate on any single cell. When desmosomes fail, the consequences are dramatic: skin blisters, life-threatening heart rhythm problems, or both.
What Desmosomes Actually Do
Every time you rub your eyes, scratch an itch, or simply move, your skin and internal organs experience mechanical stress. Desmosomes are the junctions that keep cells from being ripped apart by those forces. They connect to the intermediate filament network inside each cell, and together, desmosomes and intermediate filaments provide the mechanical stability that maintains tissue architecture when tissues are stretched or compressed.1PubMed Central. Desmosomes and Intermediate Filaments: Their Consequences for Tissue Mechanics Think of it this way: intermediate filaments are like rope inside each cell, and desmosomes are the knots tying the ropes of adjacent cells together. The result is a tissue-wide safety net.
This role is distinct from what adherens junctions do. Adherens junctions connect to the actin cytoskeleton and are involved in sensing and transmitting mechanical forces. Desmosomes, by contrast, are more about passive resistance. They maintain cohesion so the tissue does not fall apart under load. Experiments using molecular tension sensors have shown that the desmosomal protein desmoplakin bears piconewton-scale forces when external stress is applied, and that these forces relax when the stress is removed.2Nature Communications. Mechanical loading of desmosomes depends on the magnitude and orientation of external stress In plain terms, desmosomes behave like springs that tighten under pull and release when the pull stops.
How a Desmosome Is Built
A desmosome has three functional layers, each with its own set of proteins. Understanding them as layers, from outside the cell inward, makes the whole structure easier to picture.
The outermost layer sits in the narrow gap between two neighboring cells. Here, specialized adhesion proteins called desmogleins and desmocollins reach out from each cell and grab onto each other in the middle. These proteins belong to the cadherin family, a broad group of calcium-dependent adhesion molecules.3PubMed. Desmosomes and hemidesmosomes: structure and function of molecular components The pairing is almost exclusively heterophilic, meaning a desmoglein on one cell binds a desmocollin on the other, rather than two desmogleins or two desmocollins clasping together. Crystal structures of these proteins reveal that conserved charged amino acids on the surfaces of desmogleins and desmocollins repel same-type pairings through like-charge repulsion and promote cross-type pairings through opposite-charge attraction.4PubMed Central. Structural basis of adhesive binding by desmocollins and desmogleins This elegant bit of molecular design ensures that the fundamental adhesive unit is always a desmoglein-desmocollin pair. The whole interaction depends on calcium; remove calcium from the environment and the bond falls apart.5PubMed Central. Direct Ca2+-dependent heterophilic interaction between desmosomal cadherins, desmoglein and desmocollin, contributes to cell-cell adhesion
Just inside the cell membrane sits the intracellular plaque, a dense protein scaffold that acts as the go-between connecting the cadherin tails to the internal skeleton. Three-dimensional imaging of this plaque reveals two distinct layers: a lower-density layer close to the membrane and a higher-density layer further in.6PubMed Central. The three-dimensional molecular structure of the desmosomal plaque The plaque is built primarily from three proteins: plakoglobin, plakophilins, and desmoplakin. Plakoglobin is critical for connecting the transmembrane cadherins to the rest of the plaque. When plakoglobin is absent, cells can still form desmosome-like junctions, but the plaque becomes sparse and the intermediate filaments fail to anchor properly.7PubMed. Plakoglobin is required for effective intermediate filament anchorage to desmosomes
The deepest layer is where desmoplakin links the plaque to the intermediate filament network. In skin cells, these filaments are keratins; in heart muscle cells, they are desmin filaments. This final connection is what gives the desmosome its tissue-spanning mechanical strength. Without it, desmosomes are still stuck to each other between cells but are disconnected from the internal ropes that distribute force.
Where Desmosomes Are Found
Desmosomes are most abundant in tissues that endure constant mechanical stress. Skin is the champion, with desmosomes found in every layer of the epidermis. Heart muscle is a close second. But desmosomes also appear in the lining of the gut, the bladder, the uterus, and other epithelial tissues. Essentially, any tissue that needs to hold together under physical strain relies on desmosomes to some degree.
Skin
The epidermis is a stratified tissue, meaning it has multiple layers stacked on top of each other. Desmosomes appear throughout, but the specific types of desmosomal cadherins shift depending on the layer. In the deepest basal layer, desmoglein 3 and desmocollin 3 dominate. Moving outward toward the skin surface, desmoglein 1 and desmocollin 1 take over.8PubMed Central. Suprabasal desmoglein 3 expression in the epidermis of transgenic mice results in hyperproliferation and abnormal differentiation Detailed microscopy of human epidermis confirms that the ratio of desmoglein 1 to desmoglein 3 rises progressively from the basal layer to the outermost granular layer.9PubMed Central. Dsg1 and Dsg3 Composition of Desmosomes Across Human Epidermis and Alterations in Pemphigus Vulgaris Patient Skin This gradient has real medical consequences, as we will see when discussing blistering diseases.
Heart
Heart muscle cells connect end-to-end at structures called intercalated discs, which contain desmosomes, adherens junctions, and gap junctions packed closely together. In the heart, the desmosomal and adherens junction components are not neatly separated into distinct domains. Instead, desmosomal proteins like desmoplakin, plakophilin-2, plakoglobin, desmoglein 2, and desmocollin 2 intermingle with adherens junction proteins to form hybrid structures collectively called the area composita.10PubMed. The area composita of adhering junctions connecting heart muscle cells of vertebrates This intermingling has been documented across mammals and non-mammalian vertebrates alike, and the blending of junction types provides robust mechanical coupling while also supporting the electrical connections that allow the heart to beat in rhythm.11PubMed Central. Structure and regulation of desmosomes in intercalated discs: Lessons from epithelia
Desmosomes Versus Similar Structures
Cells use several different kinds of junctions, and it is easy to confuse them. Adherens junctions, tight junctions, gap junctions, and hemidesmosomes all serve different purposes, and desmosomes occupy a specific niche among them.
Adherens junctions look structurally similar to desmosomes but connect to actin filaments instead of intermediate filaments. They are better at sensing and generating mechanical forces, while desmosomes are better at absorbing them. Tight junctions seal the space between cells to control what passes through a tissue. Gap junctions are communication tunnels that let small molecules and electrical signals pass directly from one cell to the next.
Hemidesmosomes are the structure most easily confused with desmosomes, partly because of the name. But they serve a different purpose entirely: hemidesmosomes anchor the bottom of a cell to the underlying basement membrane rather than to another cell. Their transmembrane proteins are integrins, not cadherins, and they connect to a different structural substrate.3PubMed. Desmosomes and hemidesmosomes: structure and function of molecular components Both desmosomes and hemidesmosomes do share one important trait: they anchor intermediate filaments, just at different interfaces.
How Desmosomes Assemble and Remodel
Desmosomes are not permanent bolts hammered in once during development. They assemble, mature, and can be taken apart again as tissues grow, heal, or migrate. During wound healing, for example, newly formed desmosomes appear in a four-step morphological sequence: first, fine filaments extend from one cell toward another; then those filaments condense; an attachment plate forms along the inner surface of the membrane; and finally, the intermediate filaments insert into the plate.12Journal of Ultrastructure Research. Hemidesmosome and desmosome morphogenesis during epidermal wound healing
As desmosomes mature over hours, their architecture changes measurably. In cultured cells, the distance between the two desmoplakin plaques facing each other across the junction decreased from roughly 240 nanometers at three hours to about 185 nanometers by 36 hours, and the plaque length increased over the same period.13PubMed Central. Desmosomes undergo dynamic architectural changes during assembly and maturation In other words, desmosomes compact and widen as they strengthen over time.
The actin cytoskeleton, usually associated with adherens junctions, also plays a role in getting desmosomes off the ground. During cell migration, actin dynamics help bring desmosomal components together at the right place on the membrane, suggesting an underappreciated cooperation between the two cytoskeletal systems during the early stages of desmosome formation.14Experimental Cell Research. Desmosome dynamics in migrating epithelial cells requires the actin cytoskeleton
When Desmosomes Break Down
Because desmosomes are essential for holding skin and heart tissue together, diseases that compromise them tend to be severe. These diseases fall into three broad categories: autoimmune attacks, genetic mutations, and bacterial toxins.
Pemphigus
Pemphigus is a group of autoimmune blistering diseases in which the immune system produces antibodies that target desmosomal cadherins. In pemphigus vulgaris, the most common form, antibodies primarily attack desmoglein 3. When desmoglein 1 antibodies join in, blistering extends from the mucous membranes to the skin surface. In pemphigus foliaceus, the antibodies target desmoglein 1 alone, producing blistering limited to the superficial skin.15PubMed Central. Autoantibody-Specific Signalling in Pemphigus
The pattern of blistering in pemphigus maps directly onto the gradient of desmosomal cadherins in the epidermis. Because desmoglein 1 is most concentrated in the superficial layers and desmoglein 3 in the deeper layers, antibodies against desmoglein 1 cause splitting high in the epidermis, while antibodies against desmoglein 3 cause splitting lower down. This “desmoglein compensation” hypothesis explains why pemphigus foliaceus produces only superficial blisters: in the deep epidermis, desmoglein 3 can compensate for the loss of desmoglein 1, keeping cells attached. But in the superficial epidermis, where desmoglein 3 is scarce, no backup exists.
Arrhythmogenic Right Ventricular Cardiomyopathy
Arrhythmogenic right ventricular cardiomyopathy (ARVC) has been called a “disease of the desmosome” because many of the mutations that cause it sit in genes encoding desmosomal proteins at the intercalated discs of heart muscle cells.16PubMed Central. Genetics of and pathogenic mechanisms in arrhythmogenic right ventricular cardiomyopathy Mutations have been found in at least four desmosomal genes, including those for desmoplakin, plakophilin-2, plakoglobin, and desmoglein 2.17PubMed. Desmosomal dysfunction due to mutations in desmoplakin causes arrhythmogenic right ventricular dysplasia/cardiomyopathy The mutated proteins weaken cell-cell connections, leading to cardiomyocyte death, which the body replaces with fat and scar tissue. The result is an electrically unstable heart wall prone to dangerous rhythm disturbances, particularly during exercise.
Mouse models carrying a desmoplakin mutation showed increased heart cell death, fibrosis, fat accumulation, and enlarged ventricles, while mice overexpressing normal desmoplakin showed no such changes. Structural analysis of the intercalated discs in these mice revealed that the desmoplakin mutation disrupted the connection between desmoplakin and desmin filaments, unraveling the very link that gives the desmosome its mechanical purpose in heart tissue.17PubMed. Desmosomal dysfunction due to mutations in desmoplakin causes arrhythmogenic right ventricular dysplasia/cardiomyopathy
Staphylococcal Skin Infections
Some strains of Staphylococcus aureus produce exfoliative toxins that specifically cleave desmoglein 1 without touching desmoglein 3 or other cadherins.18PubMed. Toxin in bullous impetigo and staphylococcal scalded-skin syndrome targets desmoglein 1 This surgical precision explains the characteristic pattern of these infections. In bullous impetigo and staphylococcal scalded-skin syndrome, blisters form just below the outermost skin layer, the exact zone where desmoglein 1 is most concentrated and desmoglein 3 is absent. By destroying desmoglein 1, the bacteria open a space beneath the skin’s barrier, presumably allowing them to spread and proliferate. Both exfoliative toxin A and exfoliative toxin B target desmoglein 1, producing the same superficial blistering.19PubMed. Staphylococcal exfoliative toxin B specifically cleaves desmoglein 1
Inherited Skin Thickening
Mutations in the desmoglein 1 gene can also cause striate palmoplantar keratoderma, a condition marked by thickened skin on the palms and soles. Patients typically present with hyperkeratotic palms and linear ridges of thickened skin along the fingers, as well as focal thickening on the soles, toes, and heels.20PubMed Central. Striate Palmoplantar Keratoderma Resulting from a Frameshift Mutation in the Desmoglein 1 Gene Frameshift mutations that cause a loss of desmoglein 1 protein function have been identified in affected families.21PubMed. Striate palmoplantar keratoderma: a novel DSG1 mutation, combined with an LDLR mutation The palms and soles are among the body’s most mechanically stressed surfaces, so even a partial loss of desmoglein 1 function there manifests as visible disease.
Desmosomes as Signaling Hubs
For a long time, desmosomes were thought of as simple structural glue. It is now clear that their proteins also participate in cell signaling, particularly through interactions with a pathway called Wnt/β-catenin signaling, which helps control cell growth, differentiation, and fate.
The linchpin is plakoglobin. This protein is structurally similar to β-catenin, the central messenger of the Wnt signaling pathway, and the two compete with each other for binding partners. When plakoglobin binds to the transcription factor that β-catenin normally activates, it dampens the signal rather than amplifying it.22PubMed Central. Nuclear Plakoglobin Is Essential for Differentiation of Cardiac Progenitor Cells to Adipocytes in Arrhythmogenic Right Ventricular Cardiomyopathy In healthy cells, plakoglobin is mostly tied up in desmosomes, keeping it out of the nucleus and allowing β-catenin to do its job. But when desmosomal mutations release plakoglobin from the junction, it can relocate to the nucleus and suppress Wnt signaling.
This matters enormously in ARVC. When desmoplakin is knocked down in heart cells, Wnt/β-catenin signaling through the transcription factor Tcf/Lef drops by about half.23JCI Insight. Suppression of canonical Wnt/β-catenin signaling by nuclear plakoglobin recapitulates phenotype of arrhythmogenic right ventricular cardiomyopathy Wnt signaling is a major switch controlling whether cardiac progenitor cells become muscle or fat. When the signal is suppressed, the balance tips toward fat. This is the molecular explanation for why ARVC hearts fill with fatty tissue: it is not just that cells die and fat replaces them passively, but that the loss of desmosomal integrity actively reprograms surviving cells toward an adipose fate.
An Evolutionary Perspective
Desmosomes are a vertebrate innovation. Invertebrates have adherens junctions and other cell-cell connections, but true desmosomes, with their desmosomal cadherins linking intermediate filaments across the junction, appear to have arisen alongside the vertebrate lineage. This innovation may have been pivotal. The ability to anchor intermediate filaments, which are far more elastic and tough than actin filaments, gave vertebrate tissues a new degree of resilience.24Current Biology. Evolution of desmosomes and their role in anchorage and stress resilience Vertebrate skin has to handle everything from abrasion to UV exposure, and the vertebrate heart beats billions of times over a lifetime. Both tasks require junctions that can absorb repetitive stress without failing. Desmosomes, linked to intermediate filaments, provided exactly that capability.
The molecular blueprint of desmosomes mirrors that of adherens junctions: both use cadherin-family transmembrane proteins, and both use catenin-family linker proteins inside the cell. The difference is that desmosomal cadherins evolved charged surfaces that enforce heterophilic binding, and desmosomal catenins evolved to interact with plakin-family proteins like desmoplakin, which in turn bind intermediate filaments instead of actin. It looks as though evolution repurposed an existing adhesion toolkit, tweaking the molecular surfaces just enough to redirect the connection from actin to intermediate filaments, and in doing so created a structure capable of withstanding far greater mechanical abuse.
Why Desmoglein 1 Keeps Showing Up as a Target
A reader paying attention will notice a recurring character: desmoglein 1. It is the target in pemphigus foliaceus, the molecule cleaved by staphylococcal toxins, and the gene mutated in palmoplantar keratoderma. This is not a coincidence. Desmoglein 1 is the dominant desmosomal cadherin in the superficial epidermis, the zone where the skin barrier is formed and maintained. Any process that knocks out desmoglein 1, whether by autoantibody, toxin, or mutation, disrupts the same vulnerable layer. The superficial epidermis has no backup. Desmoglein 3, which could theoretically compensate, is concentrated in the deeper layers and is largely absent from the surface. This makes desmoglein 1 a single point of failure for the skin barrier, a fact that autoimmune diseases, bacteria, and inherited mutations all independently exploit.