Experts from the Institute of Molecular Genetics of the Czech Academy of Sciences discover how the plectin protein affects tissue stability in the butterfly wing disease.
Scientists discover how the plectin protein affects tissue stability in the butterfly wing disease.
The butterfly wing disease (epidermolysis bullosa) affects approximately one in 50,000 babies born. This hereditary connective tissue disorder is characterised by blistering over the entire body surface, but also affects the mucous membranes, digestive, respiratory and excretory systems. In a study published in the Journal of Cell Biology, the international research team led by Martin Gregor from the Institute of Molecular Genetics of the Czech Academy of Sciences 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 babies, as the patients are 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 treated with standard treatments, but in-depth understanding of the mechanisms of development of individual symptoms of this very complex disease could lead to future therapies.
The mechanical stability of human body tissues depends on the ability of individual cells to form strong connections (called intercellular junctions) with the surrounding cells. Of critical importance for the proper functioning of the intercellular junctions is their connection to the cytoskeleton, the dynamic three-dimensional scaffold that fills the entire cell.
Magdalena Přechová from the team of Martin Gregor (IMG), together with foreign collaborators from German and Austrian universities, recently reported that the plectin protein plays a crucial role in the organization of the cytoskeleton and intercellular junctions in epithelial cells.
Binding proteins are responsible for the formation of epithelial barriers
The plectin protein belongs to the plakin family of binding proteins and is capable of interconnecting all three types of filamentous structures, called filaments, that make up 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 cell junctions. For example, individual cells of the skin or intestinal mucosa become spaced apart under mechanical stress, allowing various pathogens (e.g., bacteria) to enter the tissue and cause inflammation (see diagram).
“Our previous studies in transgenic mouse models have shown that plectin mutations affect the ability of cells to form functional cell junctions, for example in epithelia of the intestinal mucosa or hepatic bile ducts. The inability of these mice to form a mechanically resistant “epithelial barrier” led to the development of serious pathologies such as inflammatory bowel disease (ulcerative colitis) or cholestasis, a disorder of bile secretion from the liver,” explained Martin Gregor.
A new discovery by his group has shown that plectin organizes actin and keratin filaments near intercellular junctions into a dense network that is able to reinforce intercellular connections in response to mechanical loading of the tissue. As a result, even under considerable mechanical stress, epithelial cell parting and 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 the butterfly wing disease have exceptionally sensitive skin and mucous membranes. Even mild pressure or friction leads to damage, resulting in blisters and poorly healing wounds. For this reason, some patients cannot even accept solid food. Support for people with this condition in the Czech Republic is offered by patient association DEBRA ČR (debra-cz.org).
There is currently no effective treatment for bullous epidermolysis. Physicians focus only on symptomatic treatment of this disease. Virtually the only hope for patients is gene therapy, based on the “repair” of mutated genes directly in the patient’s cells. At present, new gene therapy treatments from six pharmaceutical companies are being clinically tested.
Schematic of the organization of the cytoskeletal network and intercellular junctions in epithelial cells of a healthy individual where the protein plectin interconnects actin and keratin fibers (left) and an individual suffering from epidermolysis bullosa with a mutation in the gene encoding plectin (right).
Defective organization of keratin filaments (red) and desmosomes (yellow) in epithelial cells with an inactivated gene encoding the binding protein plectin (left). Non-functioning desmosomes and keratin filaments imaged by transmission electron microscopy (right).
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. [pubmed] [doi]