Desmosomes are specialized structures that lock neighboring cells together, acting like rivets or spot welds that hold tissues in place when they’re stretched, compressed, or otherwise stressed. They’re found wherever the body needs especially strong cell-to-cell connections, most notably in skin and heart muscle. Without functioning desmosomes, tissues literally fall apart, which is exactly what happens in several serious diseases.
How Desmosomes Hold Cells Together
Every desmosome sits at the boundary between two adjacent cells, forming a disc roughly 250 to 400 nanometers thick. The structure works in layers. Transmembrane proteins called desmosomal cadherins extend outward from each cell’s surface and interlock with cadherins from the neighboring cell, creating the adhesive bridge. There are two types of these cadherins: desmogleins and desmocollins, which pair together predominantly as mixed partners rather than identical pairs.
On the inside of each cell, the cadherin tails anchor into a dense protein assembly called the plaque. This plaque contains armadillo proteins (plakoglobin and plakophilins) that act as molecular adapters, connecting the cadherins to a large linker protein called desmoplakin. Desmoplakin then reaches deeper into the cell and grabs onto the intermediate filament network, the internal cable system that gives cells their structural resilience. Depending on the tissue, these filaments are made of different proteins: keratin in skin cells, desmin in heart muscle cells, and vimentin in other cell types.
This chain of connections, from cadherin to plaque to filament network, effectively stitches the internal skeletons of neighboring cells into a continuous mechanical web. When force hits one cell, it distributes across the tissue rather than tearing cells apart.
Why Desmosomes Are Stronger Than Other Junctions
Cells have multiple types of junctions connecting them, but desmosomes are the heavy lifters when it comes to resisting force. The other major adhesive junction, the adherens junction, connects to the actin cytoskeleton and plays an important role in sensing and transmitting mechanical signals. But in experiments where researchers knocked out key components of each junction type, the difference was stark: removing desmosomal components from skin cells caused the cell sheet to fall apart under stress, while removing the equivalent adherens junction components had no immediate effect on tissue cohesion.
A key property that makes desmosomes so tough is hyperadhesion. In mature tissues, desmosomes transition into a calcium-independent state where their adhesive bonds become exceptionally stable and resistant to disruption. Adherens junctions, by contrast, always depend on calcium to maintain their bonds, making them inherently more reversible. This ability to lock into a near-permanent grip is what allows skin to withstand constant friction and the heart to endure billions of contractions.
The desmosomal cadherins also form highly ordered arrays in their extracellular region, creating a truss-like arrangement visible under advanced imaging. This regular architecture distributes force evenly across the junction. Adherens junctions lack this kind of ordered structure in living tissue, which helps explain their relatively weaker adhesion.
Where Desmosomes Are Most Important
Desmosomes are concentrated in tissues that experience the most mechanical stress. The two standout locations are the epidermis (the outer layer of skin) and the myocardium (heart muscle).
In the epidermis, all types of desmosomal cadherins are expressed, though their distribution varies by layer. The deepest layers of skin rely on different cadherin combinations than the outermost layers, and this layered expression pattern matters for how the skin differentiates and maintains itself. The epidermis endures constant stretching, compression, and abrasion, and desmosomes are the primary reason skin cells don’t simply peel apart during daily life.
In heart muscle, desmosome expression is more restricted, using only specific cadherin types. Here, desmosomes serve double duty: they hold cardiac muscle cells together and help coordinate the mechanical forces generated during each heartbeat. The connection between desmosomes and the desmin filament network in heart cells ensures that contraction force is transmitted smoothly across the tissue.
How Desmosomes Build and Remodel
Desmosome assembly is a calcium-dependent process. Calcium causes the cadherin proteins to extend into a shape that allows them to reach across the gap between cells and bind their partners. In lab experiments, cells kept in very low calcium conditions (0.01 mM) cannot form desmosomes, but switching to normal calcium levels (1.8 mM) triggers assembly within hours.
The process isn’t instantaneous. Over the first 3 to 36 hours of assembly, the distance between the inner plaques of the two cells progressively shrinks from about 242 nanometers to 185 nanometers as the structure compacts and matures. At the same time, the plaque itself grows wider, from around 210 nanometers to 280 nanometers, as more proteins are recruited. During this calcium-dependent phase, cadherin and plaque proteins can still exchange in and out of the structure, making it somewhat dynamic. Only after full maturation does the desmosome transition into that locked, calcium-independent hyperadhesive state.
This flexibility is biologically useful. During wound healing and embryonic development, desmosomes need to disassemble and reassemble to allow cells to migrate and tissues to remodel. The ability to toggle between a strong locked state and a more dynamic, calcium-dependent state gives tissues the versatility to be both durable and adaptable.
Signaling Roles Beyond Structural Support
Desmosomes do more than just glue cells together. Their component proteins participate in signaling pathways that influence whether cells grow, differentiate, or die. These roles are layer-specific in skin. In the upper epidermis, desmoglein 1 promotes cell differentiation by dampening growth factor signaling. In contrast, when desmoglein 2 is experimentally forced into the upper layers where it doesn’t normally belong, it activates growth-promoting pathways and causes the epidermis to thicken abnormally.
Desmosomal proteins also play a role in how cells respond to environmental damage. Loss of desmoglein 1 can protect skin cells from UV-induced programmed cell death, while plakoglobin has been linked to both promoting and preventing cell death depending on context. These signaling functions mean that desmosome disruption can affect tissues in ways that go well beyond simple mechanical weakness.
Diseases Caused by Desmosome Dysfunction
Pemphigus
Pemphigus is an autoimmune blistering disease in which the immune system produces antibodies that attack desmosomal cadherins, destroying the adhesion between skin cells. In pemphigus vulgaris, the most common form, antibodies target desmoglein 3, which is heavily expressed in mucous membranes. Patients typically develop painful mouth erosions first. If antibodies against desmoglein 1 also develop, blistering spreads to the skin surface. A related form, pemphigus foliaceus, involves only anti-desmoglein 1 antibodies and causes superficial skin blisters without mucosal involvement.
The blistering occurs at different depths depending on which cadherins are targeted. Pemphigus vulgaris causes splitting in the lower half of the epidermis, sometimes producing a characteristic “tombstone” pattern where the bottom row of cells remains attached to the underlying tissue while everything above separates. Pemphigus foliaceus splits the upper half of the epidermis, producing more superficial, fragile blisters.
Arrhythmogenic Cardiomyopathy
When desmosomal genes carry mutations, the heart is particularly vulnerable. Arrhythmogenic cardiomyopathy (ACM) is a condition in which heart muscle progressively weakens, develops fatty or fibrous replacement tissue, and becomes prone to dangerous rhythm disturbances. Mutations in any of the five major desmosomal genes can cause it, but mutations in the gene for plakophilin-2 are the most common culprit. Researchers have identified dozens of distinct mutations in this gene alone across populations of European descent.
Mutations in the desmoglein-2 gene account for an estimated 5 to 10% of desmosome-related ACM cases, typically through rare missense mutations. Desmocollin-2 mutations are rarer but have been identified in specific populations, including a founder mutation in the Alberta Hutterite community. Interestingly, although these same desmosomal proteins are abundant in skin, dermatological evaluations in ACM patients are not routinely performed, and the potential skin effects of cardiac desmosomal mutations remain poorly studied.