Hyper-adhesion in desmosomes: its regulation in wound healing and possible relationship to cadherin crystal structure

Abstract

The resistance of tissues to physical stress is dependent upon strong cell-cell adhesion in which desmosomes play a crucial role. We propose that desmosomes fulfil this function by adopting a more strongly adhesive state, hyper-adhesion, than other junctions. We show that the hyper-adhesive desmosomes in epidermis resist disruption by ethylene glycol bis(2-aminoethyl ether)-N,N,N′N′-tetraacetic acid (EGTA) and are thus independent of Ca2+. We propose that Ca2+ independence is the normal condition for tissue desmosomes. Ca2+ independence is associated with an organised arrangement of the intercellular adhesive material exemplified by a dense midline. When epidermis is wounded, desmosomes in the wound-edge epithelium lose hyper-adhesiveness and become Ca2+ dependent, i.e. readily dissociated by EGTA. Ca2+-dependent desmosomes lack a midline and show narrowing of the intercellular space. We suggest that this indicates a less-organised, weakly adhesive arrangement of the desmosomal cadherins, resembling classical cadherins in adherens junctions. Transition to Ca2+ dependence on wounding is accompanied by relocalisation of protein kinase C α to desmosomal plaques suggesting that an `inside-out' transmembrane signal is responsible for changing desmosomal adhesiveness. We model hyper-adhesive desmosomes using the crystal packing observed for the ectodomain of C-cadherin and show how the regularity of this 3D array provides a possible explanation for Ca2+ independence.

A novel Nrf2-miR-29-desmocollin-2 axis regulates desmosome function in keratinocytes

“…These mice develop impaired barrier function as a result of abnormalities in the cornified envelope 9 , and the desmosomal abnormalities are likely to contribute to this impairment. Reduction of Dsc2 levels may also affect cell mobility, since loss of hyper-adhesion is associated with wound re-epithelialization and since downregulation of DSC2 promoted invasiveness of oral squamous cell carcinoma cells 36,41,42 .…”

“…The reduction in Dsc2 expression in the epidermis of K5Cre-CMVcaNrf2 mice provides a likely explanation for the loss of the midline in most of the epidermal desmosomes of these mice (Fig. 4c), since midline formation correlates with hyperadhesiveness 36 and since protein levels of DSC2 specifically increased at the time of the formation of hyper-adhesive desmosomes 34 . To further test this possibility, we transfected human primary keratinocytes with a DSC2-yellow fluorescent protein (YFP) expression vector or a green fluorescent protein (GFP) control vector.…”

150thAnniversary Series: Desmosomes and Autoimmune Disease, Perspective of Dynamic Desmosome Remodeling and Its Impairments in Pemphigus

“…The dynamic weak-adhesive desmosomes, which lose their contacts already at 90 min after transferred to low Ca 2 ϩ -medium (Ca 2 ϩ -dependent; Wallis et al, 2000;Garrod et al, 2005;Kimura et al, 2007;Garrod & Kimura, 2008), are formed in both preconfl uent keratinocytes and keratinocytes at the edge of wounds in vitro, where EGFR and Src are activated for accelerating keratinocyte migration, rather than proliferation Yamada et al, 2000). On the other hand, the stable hyper-adhesive desmosomes are found in keratinocytes cultured longer than 6 days under confl uent culture conditions, which retained desmosomal contacts for several hours even after transferred to low Ca 2 ϩ -medium (Ca 2 ϩ -independent; Wallis et al, 2000;Garrod et al, 2005;Kimura et al, 2007;Garrod & Kimura, 2008).…”

“…The association of PKC α with desmosomal plaques accompanies the switch from hyper-adhesive to weak adhesive desmosomes during epidermal wound healing (Garrod et al, 2005). PVIgG, the principal antibody of which is anti-Dsg3, is also known to activate PKCs and is linked to cell -cell detachment events Seishima et al, 1997;Esaki et al, 1995).…”

“…Rather, they are dynamic units that undergo regular remodeling. Recently, two cell -cell adhesion states, " stable hyper-adhesion (Ca 2 ϩ -independent) " and " dynamic weak-adhesion (Ca 2 ϩ -dependent) " conditions, which are mutually reversible, are recognized (Garrod et al, 2005;Kimura et al, 2007;Wallis et al, 2000). Pemphigus vulgaris (PV) is an autoimmune bullous disease caused by anti-desmoglein 3 (Dsg3) antibodies (Amagai & Stanley, 2011).…”