Bidirectional regulation of desmosome hyperadhesion by keratin isotypes and desmosomal components

Abstract

Desmosomes are intercellular junctions which mediate cohesion and communication in tissues exposed to mechanical strain by tethering the intermediate filament cytoskeleton to the plasma membrane. While mature desmosomes are characterized by a hyperadhesive, Ca2+-independent state, they transiently loose this state during wound healing, pathogenesis and tissue regeneration. The mechanisms controlling the hyperadhesive state remain incompletely understood. Here, we show that upon Ca2+-induced keratinocyte differentiation, expression of keratin 17 (K17) prevents the formation of stable and hyperadhesive desmosomes, accompanied by a significant reduction of desmoplakin (DP), plakophilin-1 (PKP1), desmoglein-1 (Dsg1) and -3 (Dsg3) at intercellular cell borders. Atomic force microscopy revealed that both increased binding strength of desmoglein-3 molecules and amount of desmoglein-3 oligomers, known hallmarks of hyperadhesion, were reduced in K17- compared to K14-expressing cells. Importantly, overexpression of Dsg3 or DPII enhanced their localization at intercellular cell borders and increased the formation of Dsg3 oligomers, resulting in stable, hyperadhesive desmosomes despite the presence of K17. Notably, PKP1 was enriched in these desmosomes. Quantitative image analysis revealed that DPII overexpression contributed to desmosome hyperadhesion by increasing the abundance of K5/K17-positive keratin filaments in the proximity of desmosomes enriched in desmoglein-3. Thus, our data show that hyperadhesion can result from recruitment of keratin isotypes K5/K17 to desmosomes or from enhanced expression of DP and Dsg3 irrespective of keratin composition. The notion that hyperadhesive desmosomes failed to form in the absence of keratins underscores the essential role of keratins and suggest bidirectional control mechanisms at several levels.

Keratin 17- and PKCα-dependent transient amplification of neutrophil influx after repeated stress to the skin

“…The latter occurs despite attenuated PKCα activity in KRT17 null cells (see Fig. 5 ), suggesting that desmosomes are impacted by PKCα-independent mechanisms in the absence of K17 (47).…”

Intermediate filament proteins are reliable immunohistological biomarkers to help diagnose multiple tissue‐specific diseases

“…It has been shown that a decrease in keratin 17 expressions in Ca 2+ ‐induced keratinocyte differentiation prevents the formation of stable and hyper‐adhesive desmosomes. These results highlight the importance of keratin for the formation of these desmosomes, as desmoplakin overexpression fails to form stable desmosomes in the absence of keratin (Büchau et al, 2022). In line with the interaction between keratin and desmosome, the desmosome can arrange suitable sites for the keratin cytoskeleton.…”

Melanoma cells repress Desmoglein 1 in keratinocytes to promote tumor cell migration

“…Slug is known to be expressed in the undifferentiated basal cell compartment of the epidermis and is important in the context of epidermal wound healing ( Arnoux et al, 2008 ). Injury is also known to induce the expression of desmosome-associated stress-associated keratins like K6/16/17 that can alter desmoglein expression and function ( Büchau et al, 2022 ). While transcripts encoding these keratins were unchanged in keratinocytes treated with melanoma-conditioned media, in the future, it will be worth more broadly considering how the desmosome-intermediate filament network controls the developing melanoma niche.…”