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Frontiers in Immunology 2018Pemphigus is a severe autoimmune-blistering disease of the skin and mucous membranes caused by autoantibodies reducing desmosomal adhesion between epithelial cells.... (Review)
Review
Pemphigus is a severe autoimmune-blistering disease of the skin and mucous membranes caused by autoantibodies reducing desmosomal adhesion between epithelial cells. Autoantibodies against the desmosomal cadherins desmogleins (Dsgs) 1 and 3 as well as desmocollin 3 were shown to be pathogenic, whereas the role of other antibodies is unclear. Dsg3 interactions can be directly reduced by specific autoantibodies. Autoantibodies also alter the activity of signaling pathways, some of which regulate cell cohesion under baseline conditions and alter the turnover of desmosomal components. These pathways include Ca, p38MAPK, PKC, Src, EGFR/Erk, and several others. In this review, we delineate the mechanisms relevant for pemphigus pathogenesis based on the histology and the ultrastructure of patients' lesions. We then dissect the mechanisms which can explain the ultrastructural hallmarks detectable in pemphigus patient skin. Finally, we reevaluate the concept that the spectrum of mechanisms, which induce desmosome dysfunction upon binding of pemphigus autoantibodies, finally defines the clinical phenotype.
Topics: Animals; Autoantibodies; Desmosomes; Humans; Pemphigus; Phenotype
PubMed: 29449846
DOI: 10.3389/fimmu.2018.00136 -
Cell Communication & Adhesion Oct 2014Hyper-adhesion is a unique, strongly adhesive form of desmosomal adhesion that functions to maintain tissue integrity. In this short review, we define hyper-adhesion,... (Review)
Review
Hyper-adhesion is a unique, strongly adhesive form of desmosomal adhesion that functions to maintain tissue integrity. In this short review, we define hyper-adhesion, summarise the evidence for it in culture and in vivo, discuss its role in development, wound healing, and skin disease, and speculate about its molecular and cellular basis.
Topics: Animals; Calcium; Cell Adhesion; Cell Membrane; Desmosomes; Humans; Pemphigus; Protein Kinase C-alpha; Wound Healing
PubMed: 24978153
DOI: 10.3109/15419061.2014.930133 -
Cell and Tissue Research Jun 2015Arrhythmogenic cardiomyopathy (ACM) is an acquired progressive disease having an age-related penetrance and showing clinical manifestations usually during adolescence... (Review)
Review
Arrhythmogenic cardiomyopathy (ACM) is an acquired progressive disease having an age-related penetrance and showing clinical manifestations usually during adolescence and young adulthood. It is characterized clinically by a high incidence of severe ventricular tachyarrhythmias and sudden cardiac death and pathologically by degeneration of ventricular cardiomyocytes with replacement by fibro-fatty tissue. Whereas, in the past, the disease was considered to involve only the right ventricle, more recent clinical studies have established that the left ventricle is frequently involved. ACM is an inherited disease in up to 50% of cases, with predominantly an autosomal dominant pattern of transmission, although recessive inheritance has also been described. Since most of the pathogenic mutations have been identified in genes encoding desmosomal proteins, ACM is currently defined as a disease of desmosomes. However, on the basis of the most recent description of the intercalated disc organization and of the identification of a novel ACM gene encoding for an area composita protein, ACM can be considered as a disease of the intercalated disc, rather than only as a desmosomal disease. Despite increasing knowledge of the genetic basis of ACM, we are just beginning to understand early molecular events leading to cardiomyocyte degeneration, fibrosis and fibro-fatty substitution. This review summarizes recent advances in our comprehension of the link between the molecular genetics and pathogenesis of ACM and of the novel role of cardiac intercalated discs.
Topics: Animals; Arrhythmias, Cardiac; Cardiomyopathies; Disease Models, Animal; Humans; Intercellular Junctions; Models, Biological
PubMed: 25344329
DOI: 10.1007/s00441-014-2015-5 -
Traffic (Copenhagen, Denmark) Dec 2016Cadherins are the primary adhesion molecules in adherens junctions and desmosomes and play essential roles in embryonic development. Although significant progress has... (Review)
Review
Cadherins are the primary adhesion molecules in adherens junctions and desmosomes and play essential roles in embryonic development. Although significant progress has been made in understanding cadherin structure and function, we lack a clear vision of how cells confer plasticity upon adhesive junctions to allow for cellular rearrangements during development, wound healing and metastasis. Endocytic membrane trafficking has emerged as a fundamental mechanism by which cells confer a dynamic state to adhesive junctions. Recent studies indicate that the juxtamembrane domain of classical cadherins contains multiple endocytic motifs, or "switches," that can be used by cellular membrane trafficking machinery to regulate adhesion. The cadherin-binding protein p120-catenin (p120) appears to be the master regulator of access to these switches, thereby controlling cadherin endocytosis and turnover. This review focuses on p120 and other cadherin-binding proteins, ubiquitin ligases, and growth factors as key modulators of cadherin membrane trafficking.
Topics: Adherens Junctions; Animals; Cadherins; Cell Adhesion; Cell Membrane; Embryonic Development; Endocytosis; Humans; Protein Transport
PubMed: 27624909
DOI: 10.1111/tra.12448 -
The keratin-desmosome scaffold of internal epithelia in health and disease - The plot is thickening.Current Opinion in Cell Biology Feb 2024Keratin (K) intermediate filaments are attached to desmosomes and constitute the orchestrators of epithelial cell and tissue architecture. While their relevance in the... (Review)
Review
Keratin (K) intermediate filaments are attached to desmosomes and constitute the orchestrators of epithelial cell and tissue architecture. While their relevance in the epidermis is well recognized, our review focuses on their emerging importance in internal epithelia. The significance of keratin-desmosome scaffolds (KDSs) in the intestine is highlighted by transgenic mouse models and individuals with inflammatory bowel disease who display profound KDS alterations. In lung, high K8 expression defines a transitional cell subset during regeneration, and K8 variants are associated with idiopathic pulmonary fibrosis. Inherited variants in desmosomal proteins are overrepresented in idiopathic lung fibrosis, and familiar eosinophilic esophagitis. K18 serum fragments are established hepatocellular injury markers that correlate with the extent of histological inflammation. K17 expression is modified in multiple tumors, and K17 levels might be of prognostic relevance. These data should spur further studies on biological roles of these versatile tissue protectors and efforts on their therapeutic targeting.
Topics: Mice; Animals; Keratins; Desmosomes; Cytoskeleton; Epithelium; Intermediate Filaments
PubMed: 38000362
DOI: 10.1016/j.ceb.2023.102282 -
Biomolecules Sep 2022Cell-cell junctions comprise various structures, including adherens junctions, tight junctions, desmosomes, and gap junctions. They link cells to each other in tissues... (Review)
Review
Cell-cell junctions comprise various structures, including adherens junctions, tight junctions, desmosomes, and gap junctions. They link cells to each other in tissues and regulate tissue homeostasis in critical cellular processes. Recent advances in cell-cell junction research have led to critical discoveries. Cell-cell adhesion components are important for the invasion and metastasis of tumour cells, which are not only related to cell-cell adhesion changes, but they are also involved in critical molecular signal pathways. They are of great significance, especially given that relevant molecular mechanisms are being discovered, there are an increasing number of emerging biomarkers, targeted therapies are becoming a future therapeutic concern, and there is an increased number of therapeutic agents undergoing clinical trials. Oesophageal squamous cell carcinoma (ESCC), the most common histological subtype of oesophageal cancer, is one of the most common cancers to affect epithelial tissue. ESCC progression is accompanied by the abnormal expression or localisation of components at cell-cell junctions. This review will discuss the recent scientific developments related to the molecules at cell-cell junctions and their role in ESCC to offer valuable insights for readers, provide a global view of the relationships between position, construction, and function, and give a reference for future mechanistic studies, diagnoses, and therapeutic developments.
Topics: Humans; Esophageal Squamous Cell Carcinoma; Adherens Junctions; Intercellular Junctions; Esophageal Neoplasms; Biomarkers
PubMed: 36291586
DOI: 10.3390/biom12101378 -
World Journal of Stem Cells Mar 2023Cardiomyopathy is a pathological condition characterized by cardiac pump failure due to myocardial dysfunction and the major cause of advanced heart failure requiring... (Review)
Review
Cardiomyopathy is a pathological condition characterized by cardiac pump failure due to myocardial dysfunction and the major cause of advanced heart failure requiring heart transplantation. Although optimized medical therapies have been developed for heart failure during the last few decades, some patients with cardiomyopathy exhibit advanced heart failure and are refractory to medical therapies. Desmosome, which is a dynamic cell-to-cell junctional component, maintains the structural integrity of heart tissues. Genetic mutations in desmosomal genes cause arrhythmogenic cardiomyopathy (AC), a rare inheritable disease, and predispose patients to sudden cardiac death and heart failure. Recent advances in sequencing technologies have elucidated the genetic basis of cardiomyopathies and revealed that desmosome-related cardiomyopathy is concealed in broad cardiomyopathies. Among desmosomal genes, mutations in (which encodes PKP2) are most frequently identified in patients with AC. deficiency causes various pathological cardiac phenotypes. Human cardiomyocytes differentiated from patient-derived induced pluripotent stem cells (iPSCs) in combination with genome editing, which allows the precise arrangement of the targeted genome, are powerful experimental tools for studying disease. This review summarizes the current issues associated with practical medicine for advanced heart failure and the recent advances in disease modeling using iPSC-derived cardiomyocytes targeting desmosome-related cardiomyopathy caused by deficiency.
PubMed: 37007457
DOI: 10.4252/wjsc.v15.i3.71 -
Tissue Barriers Oct 2022Desmosomes are macromolecular cell-cell junctions critical for maintaining adhesion and resisting mechanical stress in epithelial tissue. Desmosome assembly and the...
Desmosomes are macromolecular cell-cell junctions critical for maintaining adhesion and resisting mechanical stress in epithelial tissue. Desmosome assembly and the relationship between maturity and molecular architecture are not well understood. To address this, we employed a calcium switch assay to synchronize assembly followed by quantification of desmosome nanoscale organization using direct Stochastic Optical Reconstruction Microscopy (dSTORM). We found that the organization of the desmoplakin rod/C-terminal junction changed over the course of maturation, as indicated by a decrease in the plaque-to-plaque distance, while the plaque length increased. In contrast, the desmoplakin N-terminal domain and plakoglobin organization (plaque-to-plaque distance) were constant throughout maturation. This structural rearrangement of desmoplakin was concurrent with desmosome maturation measured by E-cadherin exclusion and increased adhesive strength. Using two-color dSTORM, we showed that while the number of individual E-cadherin containing junctions went down with the increasing time in high Ca, they maintained a wider desmoplakin rod/C-terminal plaque-to-plaque distance. This indicates that the maturation state of individual desmosomes can be identified by their architectural organization. We confirmed these architectural changes in another model of desmosome assembly, cell migration. Desmosomes in migrating cells, closest to the scratch where they are assembling, were shorter, E-cadherin enriched, and had wider desmoplakin rod/C-terminal plaque-to-plaque distances compared to desmosomes away from the wound edge. Key results were demonstrated in three cell lines representing simple, transitional, and stratified epithelia. Together, these data suggest that there is a set of architectural programs for desmosome maturation, and we hypothesize that desmoplakin architecture may be a contributing mechanism to regulating adhesive strength.
Topics: Desmosomes; gamma Catenin; Desmoplakins; Calcium; Cadherins
PubMed: 34983311
DOI: 10.1080/21688370.2021.2017225 -
Biochimica Et Biophysica Acta.... Feb 2020Tricellular junctions are specialized cell-cell junctions formed at sites where three epithelial or endothelial cells make contact at their apical side. By holding three... (Review)
Review
Tricellular junctions are specialized cell-cell junctions formed at sites where three epithelial or endothelial cells make contact at their apical side. By holding three cells together, tricellular junctions contribute to the maintenance of epithelial barrier function and mechanical integrity. In addition, recent studies have uncovered new functions of tricellular junctions at both cellular and physiological levels. In this review, we describe the architecture and molecular components of tricellular junctions and discuss how tricellular junctions participate in various biological processes.
Topics: Adherens Junctions; Animals; Desmosomes; Epithelial Cells; Humans; Tight Junction Proteins; Tight Junctions
PubMed: 31812626
DOI: 10.1016/j.bbamem.2019.183143 -
Frontiers in Cardiovascular Medicine 2021Arrhythmogenic cardiomyopathy (ACM) is a heritable heart muscle disease characterized by syncope, palpitations, ventricular arrhythmias and sudden cardiac death (SCD)... (Review)
Review
Arrhythmogenic cardiomyopathy (ACM) is a heritable heart muscle disease characterized by syncope, palpitations, ventricular arrhythmias and sudden cardiac death (SCD) especially in young individuals. It is estimated to affect 1:5,000 individuals in the general population, with >60% of patients bearing one or more mutations in genes coding for desmosomal proteins. Desmosomes are intercellular adhesion junctions, which in cardiac myocytes reside within the intercalated disks (IDs), the areas of mechanical and electrical cell-cell coupling. Histologically, ACM is characterized by fibrofatty replacement of cardiac myocytes predominantly in the right ventricular free wall though left ventricular and biventricular forms have also been described. The disease is characterized by age-related progression, vast phenotypic manifestation and incomplete penetrance, making proband diagnosis and risk stratification of family members particularly challenging. Key protein redistribution at the IDs may represent a specific diagnostic marker but its applicability is still limited by the need for a myocardial sample. Specific markers of ACM in surrogate tissues, such as the blood and the buccal epithelium, may represent a non-invasive, safe and inexpensive alternative for diagnosis and cascade screening. In this review, we shall cover the most relevant biomarkers so far reported and discuss their potential impact on the diagnosis, prognosis and management of ACM.
PubMed: 34950711
DOI: 10.3389/fcvm.2021.746321