The desmosome and pemphigus

Abstract

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 signiWcant mechanical stress such as stratiWed 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 Wlament 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 aVect 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 suVering from severe blistering skin diseases such as pemphigus. To develop disease-speciWc therapeutic approaches, more insights into the molecular composition and regulation of desmosomes are required.

Cleavage and Cell Adhesion Properties of Human Epithelial Cell Adhesion Molecule (HEPCAM)

“…Similar results were observed with longer contact times and higher pulling speeds (data not shown). As a positive control, we tested a cadherin-type adhesion molecule, DSG3, which is crucial for keratinocyte cohesion (45). Similar as shown previously (46), binding events occurred in roughly 15% of all force curves and were specifically reduced by an antibody targeting the adhesive part of the extracellular domain to levels we observe when measuringHEPEXinteractions.Althoughthesesinglemoleculemeasurements do not entirely rule out an adhesive function of EpCAM, they support our cell-based experiments and demonstrate that EpCAM does not show the behavior of a typical cell-cell adhesion molecule.…”

Desmosomal Cadherins and Signaling: Lessons from Autoimmune Disease

“…Thus, by now it is widely accepted in the fi eld of pemphigus research that signaling mechanisms are required for and signifi cantly contribute to loss of cell cohesion and blister formation in pemphigus. Many signaling molecules have been associated with pemphigus pathogenesis and shown to contribute to loss of cell adhesion in a variety of model systems (Getsios et al, 2010;Waschke, 2008). These include phospholipase C, Ca 2 ϩ , and protein kinase C (PKC) Osada et al, 1997;Seishima et al, 1995) as well as plakoglobin regulating the expression of Myc (Caldelari et al, 2001;Williamson et al, 2006).…”

“…This phenomenon called keratin retraction is closely paralleled by loss of keratinocyte cohesion. RhoA is inhibited in response to pemphigus autoantibodies in p38MAPK-dependent manner and activation of this GTPase blocked blister formation and enhanced insertion of keratin 14 at cell junctions (Waschke, 2008). Recently, RhoA, Rac1, and Cdc42 were shown to directly bind to Dsg3, at least in the non-desmosomal fraction, further indicating that the desmosomal cadherins regulate Rho GTPases (Tsang et al, 2012a).…”

Electron microscopy of high pressure frozen samples: bridging the gap between cellular ultrastructure and atomic resolution

“…Among the organelles originally discovered by electron microscopy are various junctions that connect lateral surfaces of neighboring epithelial cells. Desmosomes are easily recognized as plaque-like structures between adjacent cells with bundles of intermediate (cytokeratin) Wlaments emanating from their electron-dense cytoplasmic surface (Drochmans et al 1978;Waschke 2008). In electron micrographs of chemically Wxed and stained epidermis, desmosomes are characterized by a gap of a constant width of 35 nm between adjacent plasma membranes; the only additional structure visible in classical electron micrographs is an electron-dense "midline" in the gap between the two membranes (Drochmans et al 1978).…”