Desmosome dualism: most of the junction is stable but a plakophilin moiety is persistently dynamic

Desmosomes, strong cell-cell junctions of epithelia and cardiac muscle, link intermediate filaments to cell membranes and mechanically integrate cells across tissues, dissipating mechanical stress. They comprise five major protein classes – desmocollins and desmogleins (the desmosomal cadherins), plakoglobin, plakophilins and desmoplakin - whose individual contribution to the structure and turnover of desmosomes is poorly understood. Using live-cell imaging together with FRAP and FLAP we show that desmosomes consist of two contrasting protein moieties or modules: a very stable moiety of desmosomal cadherins, desmoplakin and plakoglobin, and a highly mobile plakophilin (Pkp2a). As desmosomes mature from calcium-dependence to calcium-independent hyper-adhesion, their stability increases, but Pkp2a remains highly mobile. We show that desmosome down-regulation during growth-factor-induced cell scattering proceeds by internalisation of whole desmosomes, which still retain a stable moiety and highly mobile Pkp2a. This molecular mobility of Pkp2a suggests a transient and probably regulatory role for Pkp2a in desmosomes.

Desmosomal Cadherins in Health and Disease

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. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 17 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Exploring RNAs Interactions and Polymorphisms in the Pathophysiology of Pemphigus: A Review

Background: Pemphigus consists of a group of rare autoimmune blistering diseases involving the skin and mucous membranes. Pemphigus pathophysiology is mediated by autoantibodies against two desmosomal cadherins, namely, desmoglein (Dsg) 1 and (Dsg) 3 that are present in the skin and mucosal membranes. The involvement of coding and non-coding RNAs in the pathophysiology of pemphigus has been studied in the literature. MicroRNAs are small RNAs that could also be used as diagnostic biomarkers for some autoimmune diseases. The aim of this research was to explore the potential of this specification of some RNAs to be used as biomarkers for diagnosing pemphigus or its severity. This review discussed RNA expressions in patients with pemphigus. Methods: A comprehensive search was performed on published studies from 1990 to May 2020 using different search engines including PubMed, Scopus, and Web of Science. Results: In general, 335 articles were obtained according to search keywords. Then, 41 relevant studies were selected based on the inclusion and exclusion criteria. MiR-338-3p, miR-424-5p, and miR-584-5p were among the miRNAs that were reported to be increased in pemphigus. The C3 mRNA, mRNA of CD36, mRNA of CD163, mRNA of urokinase plasminogen activator (PA), IL23R mRNA, RORγt mRNA, and human leukocyte antigen G1 (HLA-G1) mRNA were coding RNAs that increased in pemphigus in addition to the activity of the mRNA of tissue-type PA while HLA-G2 mRNA decreased in pemphigus. Conclusion: Overall, this study investigated the role of Mir-338-3p, miR-424-5p, MiR-127, miR-584-5p, and some mRNAs in pemphigus, and it was revealed that some RNAs may be impressive on pemphigus. More studies and clinical assessments need more information about the role of RNAs on pemphigus to obtain a better view of their mechanisms and use them as biomarkers for earlier diagnosis or probable treatment.

Desmosomal dualism: the core is stable while plakophilin is dynamic

Desmosomes, strong cell-cell junctions of epithelia and cardiac muscle, link intermediate filaments to cell membranes and mechanically integrate cells across tissues, dissipating mechanical stress. They comprise 5 major protein classes - desmocollins and desmogleins (the desmosomal cadherins), plakoglobin, plakophilins and desmoplakin - whose individual contribution to the structure and turnover of desmosomes is poorly understood. Using live-cell imaging together with FRAP and FLAP we show that desmosomes consist of two contrasting protein fractions or modules: a very stable desmosomal core of desmosomal cadherins and plakoglobin, and a highly mobile plakophilin. As desmosomes mature from calcium-dependence to calciumindependent hyper-adhesion, core stability increases, but Pkp2a remains highly mobile. Desmoplakin is initially mobile but stabilises with hyper-adhesion. We show that desmosome down-regulation during growth factor-induced cell scattering proceeds by internalisation of whole desmosomes, which still retain a stable core and highly mobile Pkp2a. This molecular mobility of Pkp2a suggests a transient and probably regulatory role for Pkp2a in the desmosome.

Desmosome architecture derived from molecular dynamics simulations and cryo-electron tomography

Desmosomes are cell–cell junctions that link tissue cells experiencing intense mechanical stress. Although the structure of the desmosomal cadherins is known, the desmosome architecture—which is essential for mediating numerous functions—remains elusive. Here, we recorded cryo-electron tomograms (cryo-ET) in which individual cadherins can be discerned; they appear variable in shape, spacing, and tilt with respect to the membrane. The resulting sub-tomogram average reaches a resolution of ∼26 Å, limited by the inherent flexibility of desmosomes. To address this challenge typical of dynamic biological assemblies, we combine sub-tomogram averaging with atomistic molecular dynamics (MD) simulations. We generate models of possible cadherin arrangements and perform an in silico screening according to biophysical and structural properties extracted from MD simulation trajectories. We find a truss-like arrangement of cadherins that resembles the characteristic footprint seen in the electron micrograph. The resulting model of the desmosomal architecture explains their unique biophysical properties and strength.

Clustering of desmosomal cadherins by desmoplakin is essential for cell-cell adhesion

ABSTRACTDesmoplakin (Dp) localizes to desmosomes, linking clusters of desmosomal adhesion molecules to the intermediate filament cytoskeleton. Here, we generated Dp knockout (ko) cell lines of human keratinocytes to study the impact on desmosomal adhesion molecules and desmosome turnover using atomic force microscopy and superresolution imaging. In comparison to ko of another desmosomal component, plakoglobin (Pg), loss of Dp resulted in absence of desmosomes and drastically impaired cell cohesion. In Dp ko, the desmosomal adhesion molecules desmoglein 2 (Dsg2) and desmocollin 3 (Dsc3) were redistributed into small clusters in the cell membrane with no further increase in loss of intercellular adhesion by silencing of Dsg2. This suggests that extradesmosomal cadherins do not significantly contribute to cell cohesion but rather localization within desmosomes is required. Our data outline a crucial role of Dp for both desmosomal molecule clustering and mature desmosome formation and provide novel insights into the regulation of intercellular adhesion.