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Trends in Cell Biology Nov 2013Desmosomes are intercellular junctions that anchor intermediate filaments (IFs) to the plasma membrane, forming a supracellular scaffold that provides mechanical... (Review)
Review
Desmosomes are intercellular junctions that anchor intermediate filaments (IFs) to the plasma membrane, forming a supracellular scaffold that provides mechanical resilience to tissues. This anchoring function is accomplished by specialized members of the cadherin family and associated cytoskeletal linking proteins, which together form a highly organized membrane core flanked by mirror-image cytoplasmic plaques. Due to the biochemical insolubility of desmosomes, the mechanisms that govern assembly of these components into a functional organelle remained elusive. Recently developed molecular reporters and live cell imaging approaches have provided powerful new tools to monitor this finely tuned process in real time. Here we discuss studies that are beginning to decipher the machinery and regulation governing desmosome assembly and homeostasis in situ and how these mechanisms are affected during disease pathogenesis.
Topics: Adherens Junctions; Animals; Desmosomes; Homeostasis; Humans
PubMed: 23891292
DOI: 10.1016/j.tcb.2013.06.004 -
Cell and Tissue Research Jun 2015Desmosomes are cell-cell junctions that mediate adhesion and couple the intermediate filament cytoskeleton to sites of cell-cell contact. This architectural arrangement... (Review)
Review
Desmosomes are cell-cell junctions that mediate adhesion and couple the intermediate filament cytoskeleton to sites of cell-cell contact. This architectural arrangement integrates adhesion and cytoskeletal elements of adjacent cells. The importance of this robust adhesion system is evident in numerous human diseases, both inherited and acquired, which occur when desmosome function is compromised. This review focuses on autoimmune and infectious diseases that impair desmosome function. In addition, we discuss emerging evidence that desmosomal genes are often misregulated in cancer. The emphasis of our discussion is placed on the way in which human diseases can inform our understanding of basic desmosome biology and in turn, the means by which fundamental advances in the cell biology of desmosomes might lead to new treatments for acquired diseases of the desmosome.
Topics: Animals; Desmosomes; Humans; Models, Biological; Skin Diseases
PubMed: 25795143
DOI: 10.1007/s00441-015-2155-2 -
Cell and Tissue Research Jun 2015Desmosomes are cell-cell adhesive organelles with a well-known role in forming strong intercellular adhesion during embryogenesis and in adult tissues subject to... (Review)
Review
Desmosomes are cell-cell adhesive organelles with a well-known role in forming strong intercellular adhesion during embryogenesis and in adult tissues subject to mechanical stress, such as the heart and skin. More recently, desmosome components have also emerged as cell signaling regulators. Loss of expression or interference with the function of desmosome molecules results in diseases of the heart and skin and contributes to cancer progression. However, the underlying molecular mechanisms that result in inherited and acquired disorders remain poorly understood. To address this question, researchers are directing their studies towards determining the functions that occur inside and outside of the junctions and the extent to which functions are adhesion-dependent or independent. This review focuses on recent discoveries that provide insights into the role of desmosomes and desmosome components in cell signaling and disease; wherever possible, we address molecular functions within and outside of the adhesive structure.
Topics: Animals; Desmosomes; Disease; Humans; Proteins; Signal Transduction
PubMed: 25693896
DOI: 10.1007/s00441-015-2136-5 -
Cold Spring Harbor Perspectives in... Aug 2009Desmosomes are intercellular junctions that tether intermediate filaments to the plasma membrane. Desmogleins and desmocollins, members of the cadherin superfamily,... (Review)
Review
Desmosomes are intercellular junctions that tether intermediate filaments to the plasma membrane. Desmogleins and desmocollins, members of the cadherin superfamily, mediate adhesion at desmosomes. Cytoplasmic components of the desmosome associate with the desmosomal cadherin tails through a series of protein interactions, which serve to recruit intermediate filaments to sites of desmosome assembly. These desmosomal plaque components include plakoglobin and the plakophilins, members of the armadillo gene family. Linkage to the cytoskeleton is mediated by the intermediate filament binding protein, desmoplakin, which associates with both plakoglobin and plakophilins. Although desmosomes are critical for maintaining stable cell-cell adhesion, emerging evidence indicates that they are also dynamic structures that contribute to cellular processes beyond that of cell adhesion. This article outlines the structure and function of the major desmosomal proteins, and explores the contributions of this protein complex to tissue architecture and morphogenesis.
Topics: Animals; Body Patterning; Calcium; Cell Adhesion; Cell Differentiation; Cytoplasm; Desmoplakins; Desmosomes; Developmental Biology; Drosophila; Epithelium; Humans; Mice; Plakophilins; gamma Catenin
PubMed: 20066089
DOI: 10.1101/cshperspect.a002543 -
Nature Cell Biology Jun 2023The endoplasmic reticulum (ER) forms a dynamic network that contacts other cellular membranes to regulate stress responses, calcium signalling and lipid transfer. Here,...
The endoplasmic reticulum (ER) forms a dynamic network that contacts other cellular membranes to regulate stress responses, calcium signalling and lipid transfer. Here, using high-resolution volume electron microscopy, we find that the ER forms a previously unknown association with keratin intermediate filaments and desmosomal cell-cell junctions. Peripheral ER assembles into mirror image-like arrangements at desmosomes and exhibits nanometre proximity to keratin filaments and the desmosome cytoplasmic plaque. ER tubules exhibit stable associations with desmosomes, and perturbation of desmosomes or keratin filaments alters ER organization, mobility and expression of ER stress transcripts. These findings indicate that desmosomes and the keratin cytoskeleton regulate the distribution, function and dynamics of the ER network. Overall, this study reveals a previously unknown subcellular architecture defined by the structural integration of ER tubules with an epithelial intercellular junction.
Topics: Desmosomes; Cytoskeleton; Keratins; Intermediate Filaments; Endoplasmic Reticulum
PubMed: 37291267
DOI: 10.1038/s41556-023-01154-4 -
Annual Review of Pathology Jan 2022Desmosomal cadherins are a recent evolutionary innovation that make up the adhesive core of highly specialized intercellular junctions called desmosomes. Desmosomal... (Review)
Review
Desmosomal cadherins are a recent evolutionary innovation that make up the adhesive core of highly specialized intercellular junctions called desmosomes. Desmosomal cadherins, which are grouped into desmogleins and desmocollins, are related to the classical cadherins, but their cytoplasmic domains are tailored for anchoring intermediate filaments instead of actin to sites of cell-cell adhesion. The resulting junctions are critical for resisting mechanical stress in tissues such as the skin and heart. Desmosomal cadherins also act as signaling hubs that promote differentiation and facilitate morphogenesis, creating more complex and effective tissue barriers in vertebrate tissues. Interference with desmosomal cadherin adhesive and supra-adhesive functions leads to a variety of autoimmune, hereditary, toxin-mediated, and malignant diseases. We review our current understanding of how desmosomal cadherins contribute to human health and disease, highlight gaps in our knowledge about their regulation and function, and introduce promising new directions toward combatting desmosome-related diseases.
Topics: Cadherins; Cell Adhesion; Desmocollins; Desmosomes; Humans; Signal Transduction
PubMed: 34425055
DOI: 10.1146/annurev-pathol-042320-092912 -
Histochemistry and Cell Biology Jul 2008Desmosomes are patch-like intercellular adhering junctions ("maculae adherentes"), which, in concert with the related adherens junctions, provide the mechanical strength... (Review)
Review
Desmosomes are patch-like intercellular adhering junctions ("maculae adherentes"), which, in concert with the related adherens junctions, provide the mechanical strength to intercellular adhesion. Therefore, it is not surprising that desmosomes are abundant in tissues subjected to significant mechanical stress such as stratified epithelia and myocardium. Desmosomal adhesion is based on the Ca(2+)-dependent, homo- and heterophilic transinteraction of cadherin-type adhesion molecules. Desmosomal cadherins are anchored to the intermediate filament cytoskeleton by adaptor proteins of the armadillo and plakin families. Desmosomes are dynamic structures subjected to regulation and are therefore targets of signalling pathways, which control their molecular composition and adhesive properties. Moreover, evidence is emerging that desmosomal components themselves take part in outside-in signalling under physiologic and pathologic conditions. Disturbed desmosomal adhesion contributes to the pathogenesis of a number of diseases such as pemphigus, which is caused by autoantibodies against desmosomal cadherins. Beside pemphigus, desmosome-associated diseases are caused by other mechanisms such as genetic defects or bacterial toxins. Because most of these diseases affect the skin, desmosomes are interesting not only for cell biologists who are inspired by their complex structure and molecular composition, but also for clinical physicians who are confronted with patients suffering from severe blistering skin diseases such as pemphigus. To develop disease-specific therapeutic approaches, more insights into the molecular composition and regulation of desmosomes are required.
Topics: Adherens Junctions; Animals; Armadillo Domain Proteins; Cadherins; Desmosomes; Epidermal Cells; Epidermis; Humans; Intermediate Filaments; Keratinocytes; Pemphigus; Plakins
PubMed: 18386043
DOI: 10.1007/s00418-008-0420-0 -
Frontiers in Immunology 2022Pemphigus vulgaris (PV) is an autoimmune bullous skin disease caused primarily by autoantibodies (PV-IgG) against the desmosomal adhesion proteins desmoglein (Dsg)1 and... (Review)
Review
Pemphigus vulgaris (PV) is an autoimmune bullous skin disease caused primarily by autoantibodies (PV-IgG) against the desmosomal adhesion proteins desmoglein (Dsg)1 and Dsg3. PV patient lesions are characterized by flaccid blisters and ultrastructurally by defined hallmarks including a reduction in desmosome number and size, formation of split desmosomes, as well as uncoupling of keratin filaments from desmosomes. The pathophysiology underlying the disease is known to involve several intracellular signaling pathways downstream of PV-IgG binding. Here, we summarize our studies in which we used transmission electron microscopy to characterize the roles of signaling pathways in the pathogenic effects of PV-IgG on desmosome ultrastructure in a human skin model. Blister scores revealed inhibition of p38MAPK, ERK and PLC/Ca to be protective in human epidermis. In contrast, inhibition of Src and PKC, which were shown to be protective in cell cultures and murine models, was not effective for human skin explants. The ultrastructural analysis revealed that for preventing skin blistering at least desmosome number (as modulated by ERK) or keratin filament insertion (as modulated by PLC/Ca) need to be ameliorated. Other pathways such as p38MAPK regulate desmosome number, size, and keratin insertion indicating that they control desmosome assembly and disassembly on different levels. Taken together, studies in human skin delineate target mechanisms for the treatment of pemphigus patients. In addition, ultrastructural analysis supports defining the specific role of a given signaling molecule in desmosome turnover at ultrastructural level.
Topics: Acantholysis; Animals; Blister; Desmosomes; Humans; Immunoglobulin G; Keratins; Mice; Pemphigus; p38 Mitogen-Activated Protein Kinases
PubMed: 35720332
DOI: 10.3389/fimmu.2022.884067 -
The Journal of Investigative Dermatology Feb 2022Single gene disorders are ideally suited to establish robust genotype‒phenotype correlations and provide excellent opportunities to understand molecular...
Single gene disorders are ideally suited to establish robust genotype‒phenotype correlations and provide excellent opportunities to understand molecular pathomechanisms with relevance to complex disorders. The observation that patients diagnosed with the same causative mutation can present with phenotypic disease variability illustrates the significant role of disease modifiers and warns against oversimplification. In a new article in the Journal of Investigative Dermatology, Zimmer et al. (2021) analyze two mutations located in the desmoglein (DSG) 1 transmembrane domain (TMD) and find that both mutants fail to assemble into desmosomes owing to reduced membrane trafficking and lipid raft targeting. One mutation maintained normal protein expression levels and turnover relative to those of wild-type (WT) DSG1, and behaved as a dominant negative. The second mutant showed reduced stability and increased turnover compared with WT DSG1 as well as reduced desmosome size and abundance. A full understanding of the TMD of DSG1 requires cell biological approaches, underscoring the value of cell biology in biomedical research in general.
Topics: Desmoglein 1; Desmosomes; Humans; Membrane Microdomains; Mutation
PubMed: 34799122
DOI: 10.1016/j.jid.2021.08.389 -
EGFR inhibition leads to enhanced desmosome assembly and cardiomyocyte cohesion via ROCK activation.JCI Insight Mar 2023Arrhythmogenic cardiomyopathy (AC) is a familial heart disease partly caused by impaired desmosome turnover. Thus, stabilization of desmosome integrity may provide new...
Arrhythmogenic cardiomyopathy (AC) is a familial heart disease partly caused by impaired desmosome turnover. Thus, stabilization of desmosome integrity may provide new treatment options. Desmosomes, apart from cellular cohesion, provide the structural framework of a signaling hub. Here, we investigated the role of the epidermal growth factor receptor (EGFR) in cardiomyocyte cohesion. We inhibited EGFR under physiological and pathophysiological conditions using the murine plakoglobin-KO AC model, in which EGFR was upregulated. EGFR inhibition enhanced cardiomyocyte cohesion. Immunoprecipitation showed an interaction of EGFR and desmoglein 2 (DSG2). Immunostaining and atomic force microscopy (AFM) revealed enhanced DSG2 localization and binding at cell borders upon EGFR inhibition. Enhanced area composita length and desmosome assembly were observed upon EGFR inhibition, confirmed by enhanced DSG2 and desmoplakin (DP) recruitment to cell borders. PamGene Kinase assay performed in HL-1 cardiomyocytes treated with erlotinib, an EGFR inhibitor, revealed upregulation of Rho-associated protein kinase (ROCK). Erlotinib-mediated desmosome assembly and cardiomyocyte cohesion were abolished upon ROCK inhibition. Thus, inhibiting EGFR and, thereby, stabilizing desmosome integrity via ROCK might provide treatment options for AC.
Topics: Animals; Mice; Cell Adhesion; Desmoglein 2; Desmosomes; ErbB Receptors; Erlotinib Hydrochloride; Myocytes, Cardiac; rho-Associated Kinases
PubMed: 36795511
DOI: 10.1172/jci.insight.163763