Plectin protein affects tissue stability in butterfly wing disease

24. 02. 2022

Butterfly wing disease (epidermolysis bullosa) affects approximately one in 50,000 born babies. This inherited connective tissue disease is characterized by blistering over the entire body surface but it also affects mucous membranes as well as digestive, respiratory, and excretory systems. In a study published in the Journal of Cell Biology, an international research team led by Martin Gregor from the Institute of Molecular Genetics of the CAS described the mechanism by which plectin, one of the proteins associated with the disease, controls the mechanical properties of tissues.

With the development of technologies allowing detailed analysis of the human genome, it has been discovered that the disease is caused by mutations in twenty-three different genes that control the architecture and mechanical resistance of the skin and mucous membranes. Butterfly children, as the patients are sometimes called because of the fragility of their skin, suffer from very painful symptoms, and the severe form of the disease leads to death at an early age.

Currently, this rare disease cannot be cured by standard treatment, but it is important to understand as best as possible the mechanisms of development of various symptoms of this very complex disease, which could lead to therapy in the future.

The mechanical stability of the human body tissues depends on the ability of individual cells to form strong connections (called intercellular junctions) with the surrounding cells.

Crucial to the proper functioning of intercellular junctions is their connection to the cytoskeleton, i.e., to the dynamic three-dimensional support network that fills the entire cell.

Magdalena Přechová from Martin Gregor's team at the Institute of Molecular Genetics of the Czech Academy of Sciences, together with foreign collaborators from German and Austrian universities, has recently described that plectin has a crucial role in the organization of the cytoskeleton and intercellular junctions in epithelial cells.

The binding proteins are responsible for the formation of epithelial barriers

Plectin protein belongs to the plakin family of binding proteins and can interconnect all three types of fibrous structures, called filaments, that create the cytoskeleton: actin microfilaments, keratin filaments, and microtubules. The resulting network is then anchored by plectin to the cell junctions that are localized on the cell membrane.

Mutations in the gene that encodes the plectin protein affect both the cytoskeletal architecture and the properties of the cell junctions. For example, individual cells of the skin or intestinal mucosa become disconnected under mechanical stress, allowing various pathogens (e.g. bacteria) to enter the tissue and cause inflammation (see the diagram).

"Our previous studies in transgenic mouse models have shown that plectin mutations affect the ability of cells to form functional cell junctions in, for example, the epithelia of the intestinal mucosa or hepatic bile ducts. The inability to form a mechanically resistant so-called 'epithelial barrier' led to the development of serious pathologies in these mice, such as inflammatory bowel disease (ulcerative colitis) or cholestasis, a disorder of bile secretion from the liver," explained Martin Gregor.

The new discovery by his group has shown that plectin organizes actin and keratin filaments near intercellular junctions into a dense network that can reinforce intercellular connections in response to mechanical loading of the tissue. As a result, even under considerable mechanical stress, epithelial cell disconnection and the subsequent development of inflammatory disease are prevented.

When every touch hurts

Throughout life, the human body is subjected to considerable mechanical stress. Patients suffering from butterfly wing disease have exceptionally sensitive skin and mucous membranes. Even mild pressure or friction causes damage to them, resulting in blisters and poorly healing wounds. Some patients cannot even receive solid food. In the Czech Republic, the patient association DEBRA ČR supports people with this condition.

There is currently no effective treatment for epidermolysis bullosa. Doctors focus only on treating the symptoms of this disease. Virtually, the only hope for patients is gene therapy, based on "repairing" the mutated genes directly in the patient's cells. New gene therapy treatments from six pharmaceutical companies are currently being clinically tested.

Link to the publication:

Prechova M., Adamova Z., Schweizer A. L., Maninova M., Bauer A., Kah D., Meier-Menches S. M., Wiche G., Fabry B., Gregor M.: Plectin-mediated cytoskeletal crosstalk controls cell tension and cohesion in epithelial sheets. Journal of Cell Biology 2022 https://doi.org/10.1083/jcb.202105146

Plectin protein affects tissue stability in butterfly wing disease

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