Desmosomes and Intermediate Filaments: Their Consequences for Tissue Mechanics.

Desmosomes and Intermediate Filaments: Their Consequences for Tissue Mechanics Mechthild Hatzfeld,1 René Keil,1 and Thomas M. Magin2 1 Institute of Molecular Medicine, Division of Pathobiochemistry, Martin-Luther-University Halle-Wittenberg, 06114 Halle, Germany 2 Institute of Biology, Division of Cell and Developmental Biology and Saxonian Incubator for Clinical Translation (SIKT), University of Leipzig, 04103 Leipzig, Germany Correspondence: ; Adherens junctions (AJs) and desmosomes connect the actin and keratin filament networks of adjacent cells into a mechanical unit. Whereas AJs function in mechanosensing and in transducing mechanical forces between the plasma membrane and the actomyosin cytoskeleton, desmosomes and intermediate filaments (IFs) provide mechanical stability required to maintain tissue architecture and integrity when the tissues are exposed to mechanical stress. Desmosomes are essential for stable intercellular cohesion, whereas keratins determine cell mechanics but are not involved in generating tension. Here, we summarize the current knowledge of the role of IFs and desmosomes in tissue mechanics and discuss whether the desmosome–keratin scaffold might be actively involved in mechanosensing and in the conversion of chemical signals into mechanical strength. he majority of tissues are constantly exposed to external forces, such as mechanical load, stretch, and shear stress, in addition to intrinsic forces generated by contractile elements inside tissues. Both extrinsic and intrinsic forces contribute to tissue morphogenesis, homeostasis, and regeneration and affect cell shape, proliferation, and migration (Evans et al. 2013). Sensing and transmitting forces depend to a large extent on tight interactions between cell adhesion complexes and the cytoskeleton. Mechanosensing and mechanotransduction can be defined as cellular processes that convert mechanical cues into intracellular signaling (Furuse et al. 2002; Huveneers and de Rooij 2013; Janmey et al. 2013). These processes are exemplified by T epithelia that line organ and body surfaces to provide structural support and serve as barriers against diverse external stressors such as mechanical force, pathogens, toxins, and dehydration. Epithelia contain two types of intercellular adhesion complexes: adherens junctions (AJs) and desmosomes, connected to the actin and keratin cytoskeleton, respectively (Fletcher and Mullins 2010). The detailed molecular mechanisms that underlie mechanotransduction are complex and only partially understood. Recent data indicate that mechanosensor proteins can undergo force-induced conformational changes that, in turn, induce changes in their activity or affinity for binding partners (Yonemura et al. 2010; Editors: Carien M. Niessen and Alpha S. Yap Additional Perspectives on Cell –Cell Junctions available at www.cshperspectives.org Copyright # 2017 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a029157 Cite this article as Cold Spring Harb Perspect Biol 2017;9:a029157 1 M. Hatzfeld et al. PKP1-si PKP3-si B PKP3-si p120-si Desmosomes are intercellular junctions essential for mediating strong intercellular cohesion (Garrod 2010; Green et al. 2010; Kowalczyk and Green 2013). They are composed of three protein families. The desmosomal cadherins, desmogleins (DSGs), and desmocollins (DSCs), are transmembrane proteins whose extracellular domains form the adhesive interface of the desmosome, whereas their cytoplasmic tails anchor the armadillo proteins, plakoglobin (PG/JUP), and plakophilins 1 – 3 (PKPs) to the desmosomal plaque. The armadillo proteins, in turn, bind to desmoplakin (DSP), a member of the plakin family of cytoskeleton-associated proteins. DSP links the desmosome to the keratin filament network, which is essential to provide tensile strength (Fig. 2). The importance of desmosomes for tissue integrity is highlighted by the severe skin and cardiac defects that arise in autoimmune and genetic diseases. PKP1-si p0071-si Composition and Structure of Desmosomes p120-si Control-si FUNCTION OF DESMOSOMES IN CONFERRING MECHANICAL STABILITY p0071-si Before rotation A referred to recent reviews (Meens et al. 2013; Patel and Green 2014). Control-si Huveneers and de Rooij 2013). This can finally lead to the activation of chemical signaling cascades. As discussed in Yap (2017), AJs function as mechanosensors (Huveneers and de Rooij 2013; Yao et al. 2014; Ladoux et al. 2015; Muhamed et al. 2016), whereas a role in force sensing has so far not been attributed to desmosomes. At the same time, desmosome-mediated intercellular adhesion is much stronger than AJmediated cohesion as shown by the epithelial sheet assay: Whereas depletion of the desmosomal plaque component plakophilin 1 (PKP1) in keratinocytes disrupts epithelial cohesion on application of mechanical stress, knockdown of the corresponding components from AJs, p120, or p0071/PKP4, has no immediate effect on intercellular cohesion (Fig. 1). Thus, this suggests that in tissues in which both junctions are present, AJs are important in mechanosensing, whereas desmosomes are crucial for providing mechanical stability under force. Here, we will review the contribution of the desmosome – keratin complex to mechanical integrity of epithelial barriers, in particular of the epidermis, and discuss their potential function in sensing and transmission of forces. For the role of intercellular contacts and intermediate filaments (IFs) of the heart, the reader is p0071 5 min rotation p120 PKP1 PKP3 20 min rotation α-Tubulin Figure 1. Dispase-based dissociation assay highlights the importance of desmosomes for intercellular cohesion. Only the knockdown of the desmosomal plaque protein plakophilin 1 (PKP1) severely disturbed intercellular cohesion of mouse keratinocytes grown for 24 h in a medium containing 1.2 mM Ca2þ. The knockdown of the corresponding proteins from adherens junctions (AJs), p120, or p0071/PKP4 did not interfere with mechanical resistance of mouse keratinocytes (A), although the respective protein amounts were considerably decreased as shown by western blot (B). 2 Cite this article as Cold Spring Harb Perspect Biol 2017;9:a029157 Desmosomes and Keratins in Tissue Mechanics The desmosome–keratin scaffold in cell mechanics C B A Figure 2. The desmosome –keratin complex as a micromechanical scaffold during epidermal differentiation. (A) Expression of keratins K5/14 and interaction with desmosomal protein isoforms forms stable cohesion among cells and protects basal keratinocytes against mechanical stress. Under conditions of tissue homeostasis, stable desmosome –keratin scaffolds prevail. (B) Cells react to wounding (activated keratinocytes) by modulating their micromechanical properties through altering adhesion and the cytoskeleton. Underlying mechanisms involve altered expression of isotype proteins and posttranslational modifications (...truncated)