Keratins Regulate the Adhesive Properties of Desmosomal Cadherins through Signaling

Abstract

Tightly controlled intercellular adhesion is crucial for the integrity and function of the epidermis. The keratin filament cytoskeleton anchors desmosomes, supramolecular complexes required for strong intercellular adhesion. We tested whether keratin filaments control cell adhesion by regulating the adhesive properties of desmosomal cadherins such as desmoglein (Dsg) 3. Atomic force microscopy and fluorescence recovery after photobleaching experiments showed reduced Dsg3 adhesive forces and membrane stability in murine keratinocytes lacking all keratin filaments. Impairment of the actin cytoskeleton also resulted in decreased Dsg3 immobilization but did not affect Dsg3 binding properties, indicating that the latter are exclusively controlled by keratins. Reduced binding forces were dependent on p38 mitogen-activated protein kinase activity, which was deregulated in keratin-deficient cells. In contrast, inhibition of protein kinase C signaling, which is known to be controlled by keratins, promoted and spatially stabilized Dsg3-mediated interactions in the membrane. These results show a previously unreported mechanism for how keratins stabilize intercellular adhesion on the level of single desmosomal adhesion molecules.

A new ex vivo human oral mucosa model reveals that p38 MAPK inhibition is not effective in preventing autoantibody‐induced mucosal blistering in pemphigus

“…Previous ultrastructural studies of normal human buccal epithelia also revealed reduced keratin formation in the basal mucosa . Other studies in mice skin showed a positive correlation between loss of keratins and a largely reduced size and number of desmosomes, which underscores the role of keratins in maintaining intercellular adhesion and desmosomal integrity . All of these observations suggest that compared with epidermis, mucosal desmosomes may be less mature and more fragile, and therefore mucosa may be more prone to blistering caused by pathogenic mechanisms such as direct inhibition.…”

“…31 Other studies in mice skin showed a positive correlation between loss of keratins and a largely reduced size and number of desmosomes, 32 which underscores the role of keratins in maintaining intercellular adhesion and desmosomal integrity. 33 All of these observations suggest that compared with epidermis, mucosal desmosomes may be less mature and more fragile, and therefore mucosa may be more prone to blistering caused by pathogenic mechanisms such as direct inhibition. However, it cannot be ruled out that signalling pathways other than p38MAPK are critical for autoantibody-induced loss of keratinocyte cohesion in human oral mucosa as well.…”

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

“…Previously, we reported that binding properties of desmosomal cadherins were altered in keratindeficient cells (Vielmuth et al, 2018), indicating that cytoskeletal anchorage affects the function of individual desmosomal cadherins. To assess how loss of Dp, the molecule mediating the anchorage to keratin filaments, influences the function of desmosomal cadherins, AFM measurements were used to examine single molecule binding properties of Dsg3 and Dsc3 as previously described .…”

“…Available data suggest that binding properties of desmosomal cadherins are dependent on desmosomal plaque proteins. For instance, loss of keratins weakened the binding forces of single molecule Dsg3 interactions in mouse keratinocytes (Vielmuth et al, 2018). Furthermore, modulation of the desmosomal plaque through ko of Pkp1 and Pkp3 reduced the frequency of Dsg3-mediated interactions (Fuchs et al, 2019).…”

The actin binding protein α-adducin modulates desmosomal turnover and plasticity

“…Nascent desmosomes serve as nucleation sites for keratin filaments (Godsel et al, 2005, Moch et al, 2019. Vice versa, the binding properties of desmosomal cadherins are compromised if keratins are absent, indicating an inside-out regulation of desmosomal adhesion on the single molecule level by intermediate filaments (Vielmuth et al, 2018b). However, since we did not find any alterations in the binding force of Dsg3 molecules on α-adducin ko cells, these data do not favor a model in which the cortical actin cytoskeleton shapes adhesion on a single molecule level.…”