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Frontiers in Oncology 2023Desmoglein-2 (DSG2) is a calcium-binding single pass transmembrane glycoprotein and a member of the large cadherin family. Until recently, DSG2 was thought to only... (Review)
Review
Desmoglein-2 (DSG2) is a calcium-binding single pass transmembrane glycoprotein and a member of the large cadherin family. Until recently, DSG2 was thought to only function as a cell adhesion protein embedded within desmosome junctions designed to enable cells to better tolerate mechanical stress. However, additional roles for DSG2 outside of desmosomes are continuing to emerge, particularly in cancer. Herein, we review the current literature on DSG2 in cancer and detail its impact on biological functions such as cell adhesion, proliferation, migration, invasion, intracellular signaling, extracellular vesicle release and vasculogenic mimicry. An increased understanding of the diverse repertoire of the biological functions of DSG2 holds promise to exploit this cell surface protein as a potential prognostic biomarker and/or target for better patient outcomes. This review explores the canonical and non-canonical functions of DSG2, as well as the context-dependent impacts of DSG2 in the realm of cancer.
PubMed: 38188287
DOI: 10.3389/fonc.2023.1327478 -
IScience Dec 2023Stem cells (SCs) are critical to maintain tissue homeostasis. However, it is currently not known whether signaling through cell junctions protects quiescent epithelial...
Stem cells (SCs) are critical to maintain tissue homeostasis. However, it is currently not known whether signaling through cell junctions protects quiescent epithelial SC reservoirs from depletion during disease-inflicted damage. Using the autoimmune model disease pemphigus vulgaris (PV), this study reveals an unprecedented role for a desmosomal cadherin in governing SC quiescence and regeneration through adhesion signaling in the multipotent mouse hair follicle compartment known as the bulge. Autoantibody-mediated, mechanical uncoupling of desmoglein (Dsg) 3 transadhesion activates quiescent bulge SC which lose their multipotency and stemness, become actively cycling, and finally delaminate from their epithelial niche. This then initiates a self-organized regenerative program which restores Dsg3 function and bulge morphology including SC quiescence and multipotency. These profound changes are triggered by the sole loss of functional Dsg3, resemble major signaling events in -/- mice, and are driven by SC-relevant EGFR activation and Wnt modulation requiring longitudinal repression of Hedgehog signaling.
PubMed: 38162019
DOI: 10.1016/j.isci.2023.108568 -
Journal of Extracellular Biology Oct 2023The retinal pigmented epithelium (RPE) constitutes the outer blood-retinal barrier, enables photoreceptor function of the eye, and is constantly exposed to oxidative...
The retinal pigmented epithelium (RPE) constitutes the outer blood-retinal barrier, enables photoreceptor function of the eye, and is constantly exposed to oxidative stress. As such, dysfunction of the RPE underlies pathology leading to development of age-related macular degeneration (AMD), the leading cause of vision loss among the elderly in industrialized nations. A major responsibility of the RPE is to process photoreceptor outer segments, which relies on the proper functioning of its endocytic pathways and endosomal trafficking. Exosomes and other extracellular vesicles (EVs) from RPE are an essential part of these pathways and may be early indicators of cellular stress. To test the role of small EVs (sEVs) including exosomes, that may underlie the early stages of AMD, we used a polarized primary RPE cell culture model under chronic subtoxic oxidative stress. Unbiased proteomic analyses of highly purified basolateral sEVs from oxidatively stressed RPE cultures revealed changes in proteins involved in epithelial barrier integrity. There were also significant changes in proteins accumulating in the basal-side sub-RPE extracellular matrix during oxidative stress, that could be prevented with an inhibitor of sEV release. Thus, chronic subtoxic oxidative stress in primary RPE cultures induces changes in sEV content, including basal-side specific desmosome and hemidesmosome shedding via sEVs. These findings provide novel biomarkers of early cellular dysfunction and opportunity for therapeutic intervention in age-related retinal diseases (e.g., AMD).
PubMed: 38108061
DOI: 10.1002/jex2.116 -
Frontiers in Cardiovascular Medicine 2023Arrhythmogenic cardiomyopathy/dysplasia (ACM) is an inheritable heart disease closely related to gene variations induced heart fibrofatty replacement, which increases...
BACKGROUND
Arrhythmogenic cardiomyopathy/dysplasia (ACM) is an inheritable heart disease closely related to gene variations induced heart fibrofatty replacement, which increases the risk of arrhythmia events and even sudden cardiac death. In this study, we reported a 10-year-old patient with a novel mutation diagnosed with ACM.
CASE PRESENTATION
We present the case of a 10-year-old patient admitted with recurrent palpitation, whose electrocardiogram suggested the existence of right ventricle origin premature ventricular contractions and ε wave. Furthermore, echocardiography showed an enlarged right ventricle corrected to a body surface area of 29.57 mm/m. The diagnosis of ACM was clear. Further gene sequencing revealed a novel heterozygous missense mutation of (cadherin-2) c.547C > G (p. P183A) that potentially increases ACM risk by affecting adherens junctions of the intercalated discs.
CONCLUSIONS
This is the first case of mutation (c.547C > G, p. P183A) related ACM in the Chinese population. Compared to previously reported mutations inducing ACM by affecting desmosome function, the newly reported variation revealed a novel potential mechanism that induces ACM by disturbing cell-cell adhesion.
PubMed: 38075981
DOI: 10.3389/fcvm.2023.1258807 -
British Journal of Biomedical Science 2023Autoimmune blistering diseases (AIBD) comprise a heterogeneous group of uncommon disorders of the skin and mucous membranes, characterised by antibodies targeting... (Review)
Review
Autoimmune blistering diseases (AIBD) comprise a heterogeneous group of uncommon disorders of the skin and mucous membranes, characterised by antibodies targeting structural proteins within epithelial tissue and the underlying basement membrane. There can be significant overlap in clinical presentation of these diseases and accurate diagnosis relies on the detection and characterisation of relevant autoantibodies. Immunofluorescence provides the gold-standard diagnostic tool for these diseases, identifying both tissue-bound autoantibodies in biopsy material using direct immunofluorescence and circulating antibodies in serum through indirect immunofluorescence. Following advances in the identification and subsequent characterisation of numerous antigenic targets in these diseases, the development of antigen-specific tests, in particular, enzyme-linked immunosorbent assays on serum specimens, has provided a third key tool to not only identify, but also quantify AIBD autoantibodies. This quantification has proven particularly useful in monitoring disease activity and informing clinical management decisions. Accurate diagnosis of these diseases is important since optimal treatment strategies differ between them and, prognostically, some diagnoses are associated with an increased risk of malignancy. This review outlines the molecular pathology underlying the major AIBD and describes how the three principal techniques can be used in combination, to provide best practice for diagnosis and treatment monitoring.
Topics: Humans; Autoimmune Diseases; Blister; Autoantibodies; Enzyme-Linked Immunosorbent Assay
PubMed: 38074463
DOI: 10.3389/bjbs.2023.11809 -
Virology Journal Dec 2023Coxsackievirus Group B type 5 (CVB5), an important pathogen of hand-foot-mouth disease, is also associated with neurological complications and poses a public health...
Coxsackievirus Group B type 5 (CVB5), an important pathogen of hand-foot-mouth disease, is also associated with neurological complications and poses a public health threat to young infants. Among the CVB5 proteins, the nonstructural protein 3D, known as the Enteroviral RNA-dependent RNA polymerase, is mainly involved in viral genome replication and transcription. In this study, we performed immunoprecipitation coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS) to identify host proteins that interacted with CVB5 3D polymerase. A total of 116 differentially expressed proteins were obtained. Gene Ontology analysis identified that the proteins were involved in cell development and cell adhesion, distributed in the desmosome and envelope, and participated in GTPase binding. Kyoto Encyclopedia of Genes and Genomes analysis further revealed they participated in nerve diseases, such as Parkinson disease. Among them, 35 proteins were significantly differentially expressed and the cellular protein TGF-BATA-activated kinase1 binding protein 1 (TAB1) was found to be specifically interacting with the 3D polymerase. 3D polymerase facilitated the entry of TAB1 into the nucleus and down-regulated TAB1 expression via the lysosomal pathway. In addition, TAB1 inhibited CVB5 replication via inducing inflammatory factors and activated the NF-κB pathway through IκBα phosphorylation. Moreover, the 90-96aa domain of TAB1 was an important structure for the function. Collectively, our findings demonstrate the mechanism by which cellular TAB1 inhibits the CVB5 replication via activation of the host innate immune response, providing a novel insight into the virus-host innate immunity.
Topics: Humans; NF-kappa B; Chromatography, Liquid; Tandem Mass Spectrometry; Immunity, Innate; Hand, Foot and Mouth Disease; Adaptor Proteins, Signal Transducing
PubMed: 38072991
DOI: 10.1186/s12985-023-02259-w -
International Journal of Molecular... Dec 2023Desmosomes play a key role in the regulation of cell adhesion and signaling. Dysregulation of the desmosome complex is associated with the loss of epithelial cell...
Desmosomes play a key role in the regulation of cell adhesion and signaling. Dysregulation of the desmosome complex is associated with the loss of epithelial cell polarity and disorganized tissue architecture typical of colorectal cancer (CRC). The aim of this study was to investigate and characterize the effect of miR-195-5p on desmosomal junction regulation in CRC. In detail, we proposed to investigate the deregulation of miR-195-5p and , a gene target that encodes a desmosome component in CRC patients. JUP closely interacts with desmosomal cadherins, and downstream, it regulates several intracellular transduction factors. We restored the miR-195-5p levels by transient transfection in colonic epithelial cells to examine the effects of miR-195-5p on JUP mRNA and protein expression. The JUP regulation by miR-195-5p, in turn, determined a modulation of desmosome cadherins (Desmoglein 2 and Desmocollin 2). Furthermore, we focused on whether the miR-195-5p gain of function was also able to modulate the expression of key components of Wnt signaling, such as NLK, LEF1 and Cyclin D1. In conclusion, we have identified a novel mechanism controlled by miR-195-5p in the regulation of adhesive junctions, suggesting its potential clinical relevance for future miRNA-based therapy in CRC.
Topics: Humans; gamma Catenin; Desmosomes; MicroRNAs; Wnt Signaling Pathway; Colorectal Neoplasms; Gene Expression Regulation, Neoplastic; Cell Line, Tumor; Cell Proliferation; Protein Serine-Threonine Kinases
PubMed: 38069408
DOI: 10.3390/ijms242317084 -
Cells Nov 2023The role of desmoglein-3 (DSG3) in oncogenesis is unclear. This study aimed to uncover molecular mechanisms through comparative transcriptome analysis in oral cancer...
The role of desmoglein-3 (DSG3) in oncogenesis is unclear. This study aimed to uncover molecular mechanisms through comparative transcriptome analysis in oral cancer cells, defining potential key genes and associated biological processes related to DSG3 expression. Four mRNA libraries of oral squamous carcinoma H413 cell lines were sequenced, and 599 candidate genes exhibited differential expression between DSG3-overexpressing and matched control lines, with 12 genes highly significantly differentially expressed, including 9 upregulated and 3 downregulated. Genes with known implications in cancer, such as MMP-13, KRT84, OLFM4, GJA1, AMOT and ADAMTS1, were strongly linked to DSG3 overexpression. Gene ontology analysis indicated that the DSG3-associated candidate gene products participate in crucial cellular processes such as junction assembly, focal adhesion, extracellular matrix formation, intermediate filament organisation and keratinocyte differentiation. Validation of RNA-Seq was performed through RT-qPCR, Western blotting and immunofluorescence analyses. Furthermore, using transmission electron microscopy, we meticulously examined desmosome morphology and revealed a slightly immature desmosome structure in DSG3-overexpressing cells compared to controls. No changes in desmosome frequency and diameter were observed between the two conditions. This study underscores intricate and multifaceted alterations associated with DSG3 in oral squamous carcinoma cells, implying a potential oncogenic role of this gene in biological processes that enable cell communication, motility and survival.
Topics: Humans; Carcinoma, Squamous Cell; Desmoglein 3; Desmosomes; Gene Expression Profiling; Keratinocytes; Keratins, Hair-Specific; Keratins, Type II; Mouth Neoplasms; Oncogenes; Transcriptome
PubMed: 38067138
DOI: 10.3390/cells12232710 -
Cell Death Discovery Dec 2023Arrhythmogenic cardiomyopathy (AC) is an inherited disorder characterized by progressive loss of the ventricular myocardium causing life-threatening ventricular...
Arrhythmogenic cardiomyopathy (AC) is an inherited disorder characterized by progressive loss of the ventricular myocardium causing life-threatening ventricular arrhythmias, syncope and sudden cardiac death in young and athletes. About 40% of AC cases carry one or more mutations in genes encoding for desmosomal proteins, including Desmoplakin (Dsp). We present here the first stable Dsp knock-out (KO) zebrafish line able to model cardiac alterations and cell signalling dysregulation, characteristic of the AC disease, on which environmental factors and candidate drugs can be tested. Our stable Dsp knock-out (KO) zebrafish line was characterized by cardiac alterations, oedema and bradycardia at larval stages. Histological analysis of mutated adult hearts showed reduced contractile structures and abnormal shape of the ventricle, with thinning of the myocardial layer, vessels dilation and presence of adipocytes within the myocardium. Moreover, TEM analysis revealed "pale", disorganized and delocalized desmosomes. Intensive physical training protocol caused a global worsening of the cardiac phenotype, accelerating the progression of the disease. Of note, we detected a decrease of Wnt/β-catenin signalling, recently associated with AC pathogenesis, as well as Hippo/YAP-TAZ and TGF-β pathway dysregulation. Pharmacological treatment of mutated larvae with SB216763, a Wnt/β-catenin agonist, rescued pathway expression and cardiac abnormalities, stabilizing the heart rhythm. Overall, our Dsp KO zebrafish line recapitulates many AC features observed in human patients, pointing at zebrafish as a suitable system for in vivo analysis of environmental modulators, such as the physical exercise, and the screening of pathway-targeted drugs, especially related to the Wnt/β-catenin signalling cascade.
PubMed: 38057295
DOI: 10.1038/s41420-023-01741-2 -
European Journal of Dentistry May 2024Cells are the building blocks of all living organisms. The presence of cell junctions such as tight junctions, gap junctions, and anchoring junctions between cells play...
Cells are the building blocks of all living organisms. The presence of cell junctions such as tight junctions, gap junctions, and anchoring junctions between cells play a role in cell-to-cell communication in periodontal health and disease. A literature search was done in Scopus, PubMed, and Web of Science to gather information about the effect of cell junctions on periodontal health and disease. The presence of tight junction in the oral cavity helps in cell-to-cell adhesiveness and assists in the barrier function. The gap junctions help in controlling growth and development and in the cell signaling process. The presence of desmosomes and hemidesmosomes as anchoring junctions aid in mechanical strength and tissue integrity. Periodontitis is a biofilm-induced disease leading to the destruction of the supporting structures of the tooth. The structures of the periodontium possess multiple cell junctions that play a significant role in periodontal health and disease as well as periodontal tissue healing. This review article provides an insight into the role of cell junctions in periodontal disease and health, and offers concepts for development of therapeutic strategies through manipulation of cell junctions.
PubMed: 38049123
DOI: 10.1055/s-0043-1775726