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Jennifer Karmouch, Alexandros Protonotarios, Petros Syrris
PURPOSE OF REVIEW: To date 16 genes have been associated with arrhythmogenic cardiomyopathy (ACM). Mutations in these genes can lead to a broad spectrum of phenotypic expression ranging from disease affecting predominantly the right or left ventricle, to biventricular subtypes. Understanding the genetic causes of ACM is important in diagnosis and management of the disorder. This review summarizes recent advances in molecular genetics and discusses the application of next-generation sequencing technology in genetic testing in ACM...
March 14, 2018: Current Opinion in Cardiology
Oxana Nekrasova, Robert M Harmon, Joshua A Broussard, Jennifer L Koetsier, Lisa M Godsel, Gillian N Fitz, Margaret L Gardel, Kathleen J Green
The epidermis is a multi-layered epithelium that serves as a barrier against water loss and environmental insults. Its morphogenesis occurs through a tightly regulated program of biochemical and architectural changes during which basal cells commit to differentiate and move towards the skin's surface. Here, we reveal an unexpected role for the vertebrate cadherin desmoglein 1 (Dsg1) in remodeling the actin cytoskeleton to promote the transit of basal cells into the suprabasal layer through a process of delamination, one mechanism of epidermal stratification...
March 13, 2018: Nature Communications
Mark Yulis, Miguel Quiros, Roland Hilgarth, Charles A Parkos, Asma Nusrat
Desmosomal cadherins mediate intercellular adhesion and have also been shown to regulate homeostatic signaling in epithelial cells. We have previously reported that select pro-inflammatory cytokines induce Dsg2 ectodomain cleavage and shedding from intestinal epithelial cells (IECs). Dsg2 extracellular cleaved fragments (Dsg2 ECF) function to induce paracrine pro-proliferative signaling in epithelial cells. In this study, we show that exposure of IECs to pro-inflammatory cytokines interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) resulted in Dsg2 intracellular cleavage and generation of a ~55 kDa fragment (Dsg2 ICF)...
March 9, 2018: Cell Death & Disease
Alice Giuliodori, Giorgia Beffagna, Giulia Marchetto, Chiara Fornetto, Francesco Vanzi, Stefano Toppo, Nicola Facchinello, Mattia Santimaria, Andrea Vettori, Stefania Rizzo, Mila Della Barbera, Kalliopi Pilichou, Francesco Argenton, Gaetano Thiene, Natascia Tiso, Cristina Basso
Aims: Arrhythmogenic cardiomyopathy (AC) is an inherited heart disease characterized by life-threatening ventricular arrhythmias and fibro-fatty replacement of the myocardium. More than 60% of AC patients show pathogenic mutations in genes encoding for desmosomal proteins. By focusing our attention on the AC8 form, linked to the junctional protein Desmoplakin (DSP), we present here a zebrafish model of DSP deficiency, exploited to identify early changes of cell signalling in the cardiac region...
March 7, 2018: Cardiovascular Research
Valérie Besnard, Rania Dagher, Tania Madjer, Audrey Joannes, Madeleine Jaillet, Martin Kolb, Philippe Bonniaud, Lynne A Murray, Matthew A Sleeman, Bruno Crestani
Periplakin is a component of the desmosomes that acts as a cytolinker between intermediate filament scaffolding and the desmosomal plaque. Periplakin is strongly expressed by epithelial cells in the lung and is a target antigen for autoimmunity in idiopathic pulmonary fibrosis. The aim of this study was to determine the role of periplakin during lung injury and remodeling in a mouse model of lung fibrosis induced by bleomycin. We found that periplakin expression was downregulated in the whole lung and in alveolar epithelial cells following bleomycin-induced injury...
March 8, 2018: JCI Insight
Luca Giannetti, Luigi Generali, Carlo Bertoldi
Involvement of the oral mucosa in patients affected by Pemphigus Vulgaris (PV), Paraneoplastic, IgA Pemphigus and in some cases of Iatrogenic Pemphigus is common, and precede skin lesions in the majority of cases. Intraepidermal bullae are caused by acantholysis, induced by IgG autoantibodies directed against the desmosomes and the domain of numerous keratinocytes self-antigens desmogleins (namely cadherins), thus supporting the autoimmune nature of the disease. Apoptosis may contribute to the acantholysis...
March 6, 2018: Giornale Italiano di Dermatologia e Venereologia: Organo Ufficiale, Società Italiana di Dermatologia e Sifilografia
Bieke Vanslembrouck, Anna Kremer, Benjamin Pavie, Frans van Roy, Saskia Lippens, Jolanda van Hengel
The intercalated disc (ID) contains different kinds of intercellular junctions: gap junctions (GJs), desmosomes and areae compositae, essential for adhesion and communication between adjacent cardiomyocytes. The junctions can be identified based on their morphology when imaged using transmission electron microscopy (TEM), however, only with very limited information in the z-dimension. The application of volume EM techniques can give insight into the three-dimensional (3-D) organization of complex biological structures...
March 5, 2018: Histochemistry and Cell Biology
Fabien Gava, Lise Rigal, Odile Mondesert, Elise Pesce, Bernard Ducommun, Valérie Lobjois
BACKGROUND: Cancer cell aggregation is a key process involved in the formation of clusters of circulating tumor cells. We previously reported that cell-cell adhesion proteins, such as E-cadherin, and desmosomal proteins are involved in cell aggregation to form clusters independently of cell migration or matrix adhesion. Here, we investigated the involvement of gap junction intercellular communication (GJIC) during anchorage-independent clustering of MCF7 breast adenocarcinoma cells. METHODS: We used live cell image acquisition and analysis to monitor the kinetics of MCF7 cell clustering in the presence/absence of GJIC pharmacological inhibitors and to screen a LOPAC® bioactive compound library...
February 27, 2018: BMC Cancer
Khalaf Kridin
Pemphigus forms a group of rare autoimmune bullous diseases that affect the skin and mucous membranes. This group has a chronic course leading to high morbidity and mortality. It is characterized by the production of pathogenic autoantibodies directed against different proteins of the desmosome, leading histologically to intraepidermal cleavage, and clinically to vesicles and erosions on the epithelium of the mucous membranes and/or the skin. The diagnosis of the subtype of pemphigus is based on clinical features, the level of histologic cleavage, and the identification of the antigens recognized by circulating autoantibodies by immunoserological analyses...
February 26, 2018: Immunologic Research
María D Vázquez-Carretero, Pablo García-Miranda, María S Balda, Karl Matter, María J Peral, Anunciación A Ilundain
Disabled-1 (Dab1) is an essential intracellular adaptor protein in the reelin pathway. Our previous studies in mice intestine showed that Dab1 transmits the reelin signal to cytosolic signalling pathways. Here, we determine the Dab1 isoform expressed in rodent small and large intestine, its subcellular location and co-localization with clathrin, caveolin-1 and N-Wasp. PCR and sequencing analysis reveal that rodent small and large intestine express a Dab1 isoform that misses three (Y198 , Y200 and Y220 ) of the five tyrosine phosphorylation sites present in brain Dab1 isoform (canonical) and contains nuclear localization and export signals...
February 19, 2018: Biochimica et Biophysica Acta
Young-Eun Cho, Li-Rong Yu, Mohamed A Abdelmegeed, Seong-Ho Yoo, Byoung-Joon Song
BACKGROUND & AIMS: Binge alcohol causes gut leakiness, contributing to increased endotoxemia and inflammatory liver injury, although the molecular mechanisms are still elusive. This study was aimed at investigating the roles of apoptosis of enterocytes and nitration followed by degradation of intestinal tight junction (TJ) and adherent junction (AJ) proteins in binge alcohol-induced gut leakiness. METHODS: The levels of intestinal (ileum) junctional complex proteins, oxidative stress markers and apoptosis-related proteins in rodents, T84 colonic cells and autopsied human ileums were determined by immunoblot, immunoprecipitation, immunofluorescence, and mass-spectral analyses...
February 16, 2018: Journal of Hepatology
Li Wang, Shenghua Liu, Hongliang Zhang, Shengshou Hu, Yingjie Wei
Arrhythmogenic cardiomyopathy (AC) is an inherited disorder that is predominantly present in the right ventricular myocardium. Mutations in the genes encoding the desmosomal protein are thought to underlie the pathogenesis of AC. Since AC is genetically heterogeneous and phenotypically diverse, modifier genes and environmental factors have an important role in disease expression. The aim of the present study was to identify AC-associated desmosomal gene variations, and examine the expression levels of intercalated disc proteins in AC patients who carry the variations (DSG2 p...
March 2018: Experimental and Therapeutic Medicine
Volker Spindler, Jens Waschke
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...
2018: Frontiers in Immunology
Laura E Melnick, Jenna M Beasley, Randi Kim, Nooshin Brinster, Kristen Lo Sicco
Paraneoplastic Pemphigus (PNP) is a rare and often fatal autoimmune mucocutaneous blistering disease associated with an underlying malignancy. It is thought to be caused by antibodies to tumor antigenscross-reacting with epithelial antigens, specifically desmosomal and hemidesmosomal antigens. There are at least five clinical morphologic variants of PNP, with the earliest and most consistent finding beingsevere stomatitis. Diagnosis of PNP requires direct immunofluorescence of perilesional skin and indirect immunofluorescence...
December 15, 2017: Dermatology Online Journal
Mona C Gjessing, Maria Aamelfot, William N Batts, Sylvie L Benestad, Ole B Dale, Even Thoen, Simon C Weli, James R Winton
Gill disease in Atlantic salmon, Salmo salar L., causes big losses in the salmon farming industry. Until now, tools to cultivate microorganisms causing gill disease and models to study the gill responses have been lacking. Here we describe the establishment and characterization of two cell lines from the gills of Atlantic salmon. Atlantic salmon gill cell ASG-10 consisted of cells staining for cytokeratin and e-cadherin and with desmosomes as seen by transmission electron microscopy suggesting the cells to be of epithelial origin...
2018: PloS One
Tomoko Sumitomo, Yasushi Mori, Yuumi Nakamura, Mariko Honda-Ogawa, Seitaro Nakagawa, Masaya Yamaguchi, Hiroyuki Matsue, Yutaka Terao, Masanobu Nakata, Shigetada Kawabata
Streptococcus pyogenes is responsible for a wide variety of cutaneous infections ranging from superficial impetigo to fulminant invasive necrotizing fasciitis. Dysfunction of desmosomes is associated with the pathogenesis of cutaneous diseases. We identified streptococcal pyrogenic exotoxin B (SpeB) as a proteolytic factor that cleaves the extracellular domains of desmoglein 1 and 3. In an epicutaneous infection model, lesional skin infected with an speB deletion mutant were significantly smaller as compared to those caused by the wild-type strain...
2018: Frontiers in Cellular and Infection Microbiology
Nicole A Najor
Tissue integrity is crucial for maintaining the homeostasis of living organisms. Abnormalities that affect sites of cell-cell contact can cause a variety of debilitating disorders. The desmosome is an essential cell-cell junctional protein complex in tissues that undergo stress, and it orchestrates intracellular signal transduction. Desmosome assembly and junctional integrity are required to maintain the overall homeostasis of a tissue, organ, and organism. This review discusses the desmosome and the human diseases associated with its disruption...
January 24, 2018: Annual Review of Pathology
Advithi Rangaraju, Shuba Krishnan, G Aparna, Satish Sankaran, Ashraf U Mannan, B Hygriv Rao
Electrical storm (ES) is a life threatening clinical situation. Though a few clinical pointers exist, the occurrence of ES in a patient with remote myocardial infarction (MI) is generally unpredictable. Genetic markers for this entity have not been studied. In the present study, we carried out genetic screening in patients with remote myocardial infarction presenting with ES by next generation sequencing and identified 25 rare variants in 19 genes predominantly in RYR2, SCN5A, KCNJ11, KCNE1 and KCNH2, CACNA1B, CACNA1C, CACNA1D and desmosomal genes - DSP and DSG2 that could potentially be implicated in electrical storm...
January 30, 2018: Indian Pacing and Electrophysiology Journal
Zinaida Dedeić, Gopinath Sutendra, Ying Hu, Kathryn Chung, Elizabeth A Slee, Michael J White, Felix Y Zhou, Robert D Goldin, David J P Ferguson, Debra McAndrew, Jurgen E Schneider, Xin Lu
Desmosome components are frequently mutated in cardiac and cutaneous disorders in animals and humans and enhanced inflammation is a common feature of these diseases. Previous studies showed that inhibitor of Apoptosis Stimulating p53 Protein (iASPP) regulates desmosome integrity at cell-cell junctions and transcription in the nucleus, and its deficiency causes cardiocutaneous disorder in mice, cattle, and humans. As iASPP is a ubiquitously expressed shuttling protein with multiple functions, a key question is whether the observed cardiocutaneous phenotypes are caused by loss of a cell autonomous role of iASPP in cardiomyocytes and keratinocytes specifically or by a loss of iASPP in other cell types such as immune cells...
January 19, 2018: Cell Death and Differentiation
Akemi Ishida-Yamamoto, Satomi Igawa, Mari Kishibe, Masaru Honma
Desmosomes provide the main intercellular adhesive properties between epidermal keratinocytes. Their distribution becomes uneven in severe dermatitis, multiple allergies and metabolic wasting syndrome due to desmoglein 1 deficiency and the loss of intercellular adhesion or acantholysis. When keratinocytes differentiate from granular cells into cornified cells, desmosomes are transformed into corneodesmosomes and can provide stronger intercellular adhesion. Degradation of corneodesmosomes is a tightly regulated process involving a number of proteases and their inhibitors...
January 19, 2018: Journal of Dermatology
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