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Frontiers in Immunology 2018Pemphigus vulgaris (PV) is a potentially life-threatening mucocutaneous autoimmune blistering disease. Patients develop non-healing erosions and blisters due to... (Review)
Review
Pemphigus vulgaris (PV) is a potentially life-threatening mucocutaneous autoimmune blistering disease. Patients develop non-healing erosions and blisters due to cell-cell detachment of keratinocytes (acantholysis), with subsequent suprabasal intraepidermal splitting. Identified almost 30 years ago, desmoglein-3 (Dsg3), a Ca-dependent cell adhesion molecule belonging to the cadherin family, has been considered the "primary" autoantigen in PV. Proteomic studies have identified numerous autoantibodies in patients with PV that have known roles in the physiology and cell adhesion of keratinocytes. Antibodies to these autoantibodies include desmocollins 1 and 3, several muscarinic and nicotinic acetylcholine receptor subtypes, mitochondrial proteins, human leukocyte antigen molecules, thyroid peroxidase, and hSPCA1-the Ca/Mn-ATPase encoded by ATP2C1, which is mutated in Hailey-Hailey disease. Several studies have identified direct pathogenic roles of these proteins, or synergistic roles when combined with Dsg3. We review the role of these direct and indirect mechanisms of non-desmoglein autoantibodies in the pathogenesis of PV.
Topics: Animals; Autoantibodies; Desmoglein 3; Desmosomes; Epitopes; Humans; Keratinocytes; Mice; Pemphigus; Pemphigus, Benign Familial
PubMed: 29915578
DOI: 10.3389/fimmu.2018.01190 -
Allergology International : Official... Jan 2018The skin is continuously exposed to external pathogens, and its barrier function is critical for skin homeostasis. Previous studies have shown that the barrier... (Review)
Review
The skin is continuously exposed to external pathogens, and its barrier function is critical for skin homeostasis. Previous studies have shown that the barrier dysfunction is one of the most predisposing factors for the development of skin allergic diseases such as atopic dermatitis. In this article, we summarize how the physical barrier of the skin is organized and review its link to the pathomechanism of skin allergic diseases. We describe the formation of the SC barrier in terms of the following five categories: 1) filaggrin metabolism; 2) cornified envelope; 3) intercellular lipids; 4) corneodesmosome; and 5) corneocyte desquamation. New approaches to restoring the skin barrier function are also discussed.
Topics: Animals; Dermatitis, Atopic; Desmosomes; Filaggrin Proteins; Humans; Intermediate Filament Proteins; Lipid Metabolism; Skin
PubMed: 29153780
DOI: 10.1016/j.alit.2017.10.002 -
JPMA. the Journal of the Pakistan... Aug 2020Cell-adhesion complex within a tissue is important for its stability, structural integrity, functioning, cellular migration and morphogenesis. Disruption of desmosomal... (Review)
Review
Cell-adhesion complex within a tissue is important for its stability, structural integrity, functioning, cellular migration and morphogenesis. Disruption of desmosomal cell-adhesions complex results in epithelial conditions such as epidermolysis bullosa and bullous pemphigoid. Desmosome assembly and disassembly is regulated post-translationally by calcium, kinase/phosphatase activity, proteolytic processing, and also through adhesive junctions. Altered functions of desmosomal proteins desmocollin and desmoglein can cause blistering disorders, such as pemphigus foliaceus and pemphigus vulgaris, and non-Hodgkin Lymphoma while defective desmoplakin can cause supra-basal clefting in epithelium and conditions such as Carvajal syndrome, palmo-plantar keratoderma etc. This review summarises major functions of demosomal complex family and how mis-regulation of demosomal structural proteins occur in pathogenesis of non-, pre- and malignant oral lesions with disrupted epithelium.
Topics: Desmosomes; Humans; Mouth Mucosa; Pemphigus
PubMed: 32794499
DOI: 10.5455/JPMA.15798 -
F1000Research 2019The development of adhesive connections between cells was critical for the evolution of multicellularity and for organizing cells into complex organs with discrete... (Review)
Review
The development of adhesive connections between cells was critical for the evolution of multicellularity and for organizing cells into complex organs with discrete compartments. Four types of intercellular junction are present in vertebrates: desmosomes, adherens junctions, tight junctions, and gap junctions. All are essential for the development of the embryonic layers and organs as well as adult tissue homeostasis. While each junction type is defined as a distinct entity, it is now clear that they cooperate physically and functionally to create a robust and functionally diverse system. During evolution, desmosomes first appeared in vertebrates as highly specialized regions at the plasma membrane that couple the intermediate filament cytoskeleton at points of strong cell-cell adhesion. Here, we review how desmosomes conferred new mechanical and signaling properties to vertebrate cells and tissues through their interactions with the existing junctional and cytoskeletal network.
Topics: Animals; Cytoskeleton; Desmosomes; Intercellular Junctions; Signal Transduction
PubMed: 31942240
DOI: 10.12688/f1000research.20942.1 -
The Journal of Investigative Dermatology Feb 2022Dominant and recessive mutations in the desmosomal cadherin, desmoglein (DSG) 1, cause the skin diseases palmoplantar keratoderma (PPK) and severe dermatitis, multiple...
Dominant and recessive mutations in the desmosomal cadherin, desmoglein (DSG) 1, cause the skin diseases palmoplantar keratoderma (PPK) and severe dermatitis, multiple allergies, and metabolic wasting (SAM) syndrome, respectively. In this study, we compare two dominant missense mutations in the DSG1 transmembrane domain (TMD), G557R and G562R, causing PPK (DSG1) and SAM syndrome (DSG1), respectively, to determine the differing pathomechanisms of these mutants. Expressing the DSG1 mutants in a DSG-null background, we use cellular and biochemical assays to reveal the differences in the mechanistic behavior of each mutant. Super-resolution microscopy and functional assays showed a failure by both mutants to assemble desmosomes due to reduced membrane trafficking and lipid raft targeting. DSG1 maintained normal expression levels and turnover relative to wildtype DSG1, but DSG1 lacked stability, leading to increased turnover through lysosomal and proteasomal pathways and reduced expression levels. These results differentiate the underlying pathomechanisms of these disorders, suggesting that DSG1 acts dominant negatively, whereas DSG1 is a loss-of-function mutation causing the milder PPK disease phenotype. These mutants portray the importance of the DSG TMD in desmosome function and suggest that a greater understanding of the desmosomal cadherin TMDs will further our understanding of the role that desmosomes play in epidermal pathophysiology.
Topics: Cell Adhesion; Cell Line, Tumor; Desmoglein 1; Desmosomal Cadherins; Desmosomes; Epidermis; Humans; Keratoderma, Palmoplantar; Loss of Function Mutation; Membrane Microdomains; Mutation, Missense; Protein Domains; Protein Stability
PubMed: 34352264
DOI: 10.1016/j.jid.2021.07.154 -
Cancer Science Jan 2024Plakophilin 3 (PKP3), a component of desmosome, is aberrantly expressed in many kinds of human diseases, especially in cancers. Through direct interaction, PKP3 binds... (Review)
Review
Plakophilin 3 (PKP3), a component of desmosome, is aberrantly expressed in many kinds of human diseases, especially in cancers. Through direct interaction, PKP3 binds with a series of desmosomal proteins, such as desmoglein, desmocollin, plakoglobin, and desmoplakin, to initiate desmosome aggregation, then promotes its stability. As PKP3 is mostly expressed in the skin, loss of PKP3 promotes the development of several skin diseases, such as paraneoplastic pemphigus, pemphigus vulgaris, and hypertrophic scar. Moreover, accumulated clinical data indicate that PKP3 dysregulates in diverse cancers, including breast, ovarian, colon, and lung cancers. Numerous lines of evidence have shown that PKP3 plays important roles in multiple cellular processes during cancer progression, including metastasis, invasion, tumor formation, autophagy, and proliferation. This review examines the diverse functions of PKP3 in regulating tumor formation and development in various types of cancers and summarizes its detailed mechanisms in the occurrence of skin diseases.
Topics: Humans; Desmosomes; Neoplasms; Plakophilins; Skin Diseases
PubMed: 38048779
DOI: 10.1111/cas.16019 -
Cells Aug 2023Desmosomes play a vital role in providing structural integrity to tissues that experience significant mechanical tension, including the heart. Deficiencies in desmosomal... (Review)
Review
Desmosomes play a vital role in providing structural integrity to tissues that experience significant mechanical tension, including the heart. Deficiencies in desmosomal proteins lead to the development of arrhythmogenic cardiomyopathy (AC). The limited availability of preventative measures in clinical settings underscores the pressing need to gain a comprehensive understanding of desmosomal proteins not only in cardiomyocytes but also in non-myocyte residents of the heart, as they actively contribute to the progression of cardiomyopathy. This review focuses specifically on the impact of desmosome deficiency on epi- and endocardial cells. We highlight the intricate cross-talk between desmosomal proteins mutations and signaling pathways involved in the regulation of epicardial cell fate transition. We further emphasize that the consequences of desmosome deficiency differ between the embryonic and adult heart leading to enhanced erythropoiesis during heart development and enhanced fibrogenesis in the mature heart. We suggest that triggering epi-/endocardial cells and fibroblasts that are in different "states" involve the same pathways but lead to different pathological outcomes. Understanding the details of the different responses must be considered when developing interventions and therapeutic strategies.
Topics: Adult; Humans; Desmosomes; Cardiomyopathies; Cell Differentiation; Epirubicin; Myocytes, Cardiac
PubMed: 37681854
DOI: 10.3390/cells12172122 -
Biomolecules Jun 2021Desmosomes are intercellular adhesion complexes involved in various aspects of epithelial pathophysiology, including tissue homeostasis, morphogenesis, and disease... (Review)
Review
Desmosomes are intercellular adhesion complexes involved in various aspects of epithelial pathophysiology, including tissue homeostasis, morphogenesis, and disease development. Recent studies have reported that the abnormal expression of various desmosomal components correlates with tumor progression and poor survival. In addition, desmosomes have been shown to act as a signaling platform to regulate the proliferation, invasion, migration, morphogenesis, and apoptosis of cancer cells. The occurrence and progression of head and neck cancer (HNC) is accompanied by abnormal expression of desmosomal components and loss of desmosome structure. However, the role of desmosomal components in the progression of HNC remains controversial. This review aims to provide an overview of recent developments showing the paradoxical roles of desmosomal components in tumor suppression and promotion. It offers valuable insights for HNC diagnosis and therapeutics development.
Topics: Cell Adhesion; Desmosomes; Head and Neck Neoplasms; Humans; Signal Transduction
PubMed: 34203070
DOI: 10.3390/biom11060914 -
Frontiers in Immunology 2019Desmosomes reinforce cohesion of epithelial cells at the interface between adjacent cells. They include the cadherin-type adhesion molecules desmoglein 1 (Dsg1) and...
Desmosomes reinforce cohesion of epithelial cells at the interface between adjacent cells. They include the cadherin-type adhesion molecules desmoglein 1 (Dsg1) and Dsg3. Pemphigus vulgaris (PV) is an autoimmune disease in which circulating autoantibodies (PV-IgG) targeting Dsg1 and 3 cause characteristic epidermal blister formation. It has been shown that PV-IgG binding induced activation of kinases such as ERK and PKC, and inhibition of these signaling pathways prevented loss of cell cohesion in cell cultures. However, the role of Erk and PKC in blister formation and regulation of desmosome ultrastructure in human skin are unknown. Accordingly, we assessed the role of PKC and ERK signaling pathways in blister formation and regulation of desmosome ultrastructure in human epidermis. Here we performed electron microscopy analyses using human skin explants injected with PV-IgG together with inhibitors for PKC or ERK signaling. Inhibition of PKC was not effective to prevent suprabasal blister formation or ultrastructural alterations of desmosomes. In contrast, inhibition of ERK signaling significantly ameliorated blister formation and decrease in the number of desmosomes whereas shortening and splitting of desmosomes and keratin filament insertion were not different from samples treated with PV-IgG alone. However, apical desmosomes between basal and suprabasal cells remained unaltered when ERK signaling was inhibited. Therefore, our results show that inhibition of ERK but not PKC signaling appears to be effective to ameliorate blistering and alterations of desmosome ultrastructure triggered by PV-IgG in human skin.
Topics: Desmosomes; Epidermis; Humans; MAP Kinase Signaling System; Pemphigus; Protein Kinase C
PubMed: 31867019
DOI: 10.3389/fimmu.2019.02883 -
Biochimica Et Biophysica Acta.... Sep 2020Epithelial and endothelial monolayers are multicellular sheets that form barriers between the 'outside' and 'inside' of tissues. Cell-cell junctions, made by adherens... (Review)
Review
Epithelial and endothelial monolayers are multicellular sheets that form barriers between the 'outside' and 'inside' of tissues. Cell-cell junctions, made by adherens junctions, tight junctions and desmosomes, hold together these monolayers. They form intercellular contacts by binding their receptor counterparts on neighboring cells and anchoring these structures intracellularly to the cytoskeleton. During tissue development, maintenance and pathogenesis, monolayers encounter a range of mechanical forces from the cells themselves and from external systemic forces, such as blood pressure or tissue stiffness. The molecular landscape of cell-cell junctions is diverse, containing transmembrane proteins that form intercellular bonds and a variety of cytoplasmic proteins that remodel the junctional connection to the cytoskeleton. Many junction-associated proteins participate in mechanotransduction cascades to confer mechanical cues into cellular responses that allow monolayers to maintain their structural integrity. We will discuss force-dependent junctional molecular events and their role in cell-cell contact organization and remodeling.
Topics: Adherens Junctions; Blood Pressure; Cytoskeleton; Desmosomes; Endothelial Cells; Epithelial Cells; Humans; Intercellular Junctions; Mechanical Phenomena; Membrane Proteins; Tight Junctions
PubMed: 32360073
DOI: 10.1016/j.bbamem.2020.183316