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Scaling up Single-Cell Mechanics to Multicellular Tissues – the Role of the Intermediate Filament–Desmosome Network Joshua A

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Scaling up Single-Cell Mechanics to Multicellular Tissues – the Role of the Intermediate Filament–Desmosome Network Joshua A © 2020. Published by The Company of Biologists Ltd | Journal of Cell Science (2020) 133, jcs228031. doi:10.1242/jcs.228031 REVIEW SUBJECT COLLECTION: MECHANOTRANSDUCTION Scaling up single-cell mechanics to multicellular tissues – the role of the intermediate filament–desmosome network Joshua A. Broussard1,2,7,*, Avinash Jaiganesh2, Hoda Zarkoob2, Daniel E. Conway3, Alexander R. Dunn4, Horacio D. Espinosa5, Paul A. Janmey6 and Kathleen J. Green1,2,7,* ABSTRACT and cardiomyopathies (Mammoto et al., 2013; Jaalouk and Cells and tissues sense, respond to and translate mechanical forces Lammerding, 2009; Barnes et al., 2017; Lampi and Reinhart- into biochemical signals through mechanotransduction, which King, 2018). governs individual cell responses that drive gene expression, Cells and tissues both sense and respond to mechanical forces metabolic pathways and cell motility, and determines how cells through a process called mechanotransduction, whereby work together in tissues. Mechanotransduction often depends on mechanical forces are translated into biochemical signals. This cytoskeletal networks and their attachment sites that physically process depends on cytoskeletal networks that physically couple couple cells to each other and to the extracellular matrix. One way that cells to their extracellular environment and to other cells within cells associate with each other is through Ca2+-dependent adhesion tissues through adhesive junctions. The cytoskeleton of animal cells molecules called cadherins, which mediate cell–cell interactions comprises three main filamentous networks: filamentous actin through adherens junctions, thereby anchoring and organizing the (F-actin), microtubules and intermediate filaments (IFs) (Fig. 1A). cortical actin cytoskeleton. This actin-based network confers dynamic These cytoskeletal networks are in continuous communication properties to cell sheets and developing organisms. However, these through physical linkages and signaling crosstalk, cooperating to contractile networks do not work alone but in concert with other regulate cell behaviors, such as cell migration and division, as well cytoarchitectural elements, including a diverse network of intermediate as governing cell mechanics (Fig. 1B) (Chang and Goldman, 2004; filaments. This Review takes a close look at the intermediate filament Huber et al., 2015). Furthermore, mechanical forces are sensed and network and its associated intercellular junctions, desmosomes. We transmitted by adhesive complexes that form links to either the provide evidence that this system not only ensures tissue integrity, but extracellular environment or other cells, and intracellularly interact also cooperates with other networks to create more complex tissues with the cytoskeleton (Schwartz and DeSimone, 2008; De Pascalis with emerging properties in sensing and responding to increasingly et al., 2018). Linkage of IFs and F-actin to the extracellular substrate stressful environments. We will also draw attention to how defects in is provided by hemidesmosomes and focal adhesions, while linkage – intermediate filament and desmosome networks result in both chronic of IFs and F-actin at sites of cell cell contact is provided by and acquired diseases. desmosomes and adherens junctions (Fig. 2), respectively. While defining mechanical properties of individual IFs has been KEY WORDS: Mechanotransduction, Cadherin, Cytoskeleton, a research focus for decades, less is known about how IFs and their Cell–cell adhesion, Desmosome, Intermediate filaments plasma membrane connections are integrated with other cytoskeletal elements to control cell and tissue mechanics and Introduction signaling. Here, we provide a summary of our current understanding Cells and tissues are primarily regulated by two main types of of the mechanobiology of the IF-based adhesive network, with a stimuli: chemical and physical. The advent of modern molecular focus on discussing the emerging functions of desmosomes and biology has accelerated our understanding of biochemical their integration with other cytoskeleton–plasma membrane influences over biology, but these signals are insufficient to networks. We highlight evidence that, like IFs, desmosomes not explain the complexity of life. More recently, it has become only play a role in tissue integrity but actively contribute to cellular increasingly apparent how pervasive the effects of physical signals mechanotransduction pathways. are in essentially all aspects of cell and tissue biology. For example, mechanical forces play fundamental roles in cell and tissue growth, IFs regulate cell mechanics and are mechanosensitive differentiation, morphogenesis, tissue repair and even in disease IFs were the last of the three major cytoskeletal elements confirmed states, including cancer, pulmonary disease, muscular dystrophy as distinct entities (Lazarides, 1980; Oshima, 2007). They are vital to the integrity of tissues that require mechanical resilience, such as muscle and stratified epithelia (Vassar et al., 1991; Galou et al., 1Departments of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. 2Pathology, Feinberg School of Medicine, 1997). Loss of or aberrant gain of IF function is linked to a wide Northwestern University, Chicago, IL 60611, USA. 3Department of Biomedical array of mechanically associated human diseases, including Engineering, Virginia Commonwealth University, Richmond, VA 23284, USA. 4Department of Chemical Engineering, Stanford University, Stanford, CA 94305, myopathies, skin blistering and fragility, and neurogenerative USA. 5Department of Mechanical Engineering, McCormick School of Engineering, disorders (Lane, 2006; Omary et al., 2004). Thus, IFs are prime Northwestern University, Evanston, IL 60208, USA. 6Department of Physiology, candidates to play roles in mechanobiology and transduction, but University of Pennsylvania, Philadelphia, PA 19104, USA. 7Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611, USA. how they perform these roles in an integrated fashion with the other cytoskeletal components is poorly understood. *Authors for correspondence ([email protected]; There are 70 genes encoding IF proteins (Herrmann et al., 2009), [email protected]) some with multiple splice forms (Hol et al., 2003). There are six J.A.B., 0000-0002-3752-7880 main groups, or ‘types’, of IF, based on sequence similarity, and Journal of Cell Science 1 REVIEW Journal of Cell Science (2020) 133, jcs228031. doi:10.1242/jcs.228031 A F-actin Keratin IF Microtubules Fig. 1. Architecture of the three main cytoskeletal systems. (A) Immunofluorescence staining shows the organization of the F-actin, keratin IF and microtubule cytoskeletons in human epidermal keratinocytes. Plakoglobin (PG) is used to show regions of cell–cell contact and F-actin Keratin Tu b u li n nuclei are shown in blue with DAPI. PG PG PG (B) Schematic representations of the indicated filamentous cytoskeletons and associated cell–cell adhesive complexes, as well as an overlay to illustrate their interconnected nature. Gray outlines B represent cell–cell junctional areas and ovals represent nuclei. Images supplied by the laboratory of K.J.G. Adherens junctions Desmosomes Microtubules F-actin Intermediate filaments Overlay these are expressed in tissue-specific patterns, namely, type I/II In addition to their protective role, cytoplasmic IFs, along with F- keratins, type III vimentin/desmin, type IV neurofilaments, type V actin and microtubules, are involved in cellular responses to force. nuclear lamins and type VI lens filaments (Table 1). This Review For example, cells respond to applied cyclical stretching by will focus on cytoplasmic IFs. reorienting their cell body axis approximately perpendicular to the Cytoplasmic IFs play an important role in protecting cells from applied load (Buck, 1980). Reorientation depends on the magnitude stress, and mutations in IF proteins are associated with human of the applied stretch, with higher magnitudes inducing further diseases that manifest downstream of multiple types of stress reorientation (Wang et al., 1995; Takemasa et al., 1997). (Toivola et al., 2010). An example is epidermolysis bullosa simplex Interestingly, cytoskeletal reorganization precedes cell body (EBS), a blistering disease caused by mutated keratin 5 or 14 reorientation, suggesting this is an active adaptation mechanism (Coulombe et al., 1991; Russell et al., 2004; Stephens et al., 1995). (Zielinski et al., 2018). Strain-induced reorientation occurs for all One type of stress that can induce blistering is mechanical force. three major cytoskeletal systems, with distinctive timing: F-actin Stretching cells expressing EBS mutant keratins has been reported reorients first, followed by microtubules and then IFs (Zielinski to induce IF network fragmentation and disassembly of their et al., 2018; Kreplak and Fudge, 2007). F-actin is remodeled such anchoring adhesive structures (Russell et al., 2004). In this case, the that filament bundles orient perpendicular to the applied cyclical morphology of IF networks comprising EBS mutant keratin is force (Takemasa et al., 1997; Iba and Sumpio, 1991; Chen et al., similar to controls prior to stretch (Russell et al., 2004), suggesting 2013). While microtubules reorient, cell reorientation does not that force can act as a mechanotrigger for disease progression. depend on microtubules (Goldyn et al., 2010; Wang et al., 2001) but However, EBS keratin IF fragmentation
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