Cytoskeleton in motion: the dynamics of keratin intermediate filaments in epithelia

Abstract

Epithelia are exposed to multiple forms of stress. Keratin intermediate filaments are abundant in epithelia and form cytoskeletal networks that contribute to cell type-specific functions, such as adhesion, migration, and metabolism. A perpetual keratin filament turnover cycle supports these functions. This multistep process keeps the cytoskeleton in motion, facilitating rapid and protein biosynthesis-independent network remodeling while maintaining an intact network. The current challenge is to unravel the molecular mechanisms underlying the regulation of the keratin cycle in relation to actin and microtubule networks and in the context of epithelial tissue function.

Figure 1.

The keratin cycle. Soluble keratin oligomers assemble into particles in the cell periphery in proximity to focal adhesion sites (nucleation). These particles grow (elongation) and move toward the cell center in an actin-dependent process (transport). Subsequently, elongated KF particles are incorporated into the peripheral KF network (integration). Filament bundling occurs during further centripetal translocation toward the nucleus (transport). Soluble oligomers dissociate (disassembly), diffuse throughout the cytoplasm (diffusion), and are reutilized for another cycle of KF formation in the cell periphery. Alternatively, bundled filaments are stabilized (maturation), forming, e.g., the stable perinuclear cage.

Figure 2.

Steps of the keratin cycle. Representative images (inverse presentation), taken from time-lapse fluorescence microscopy of cultured cells producing fluorescent keratins (see Video 1), that illustrate the steps of the keratin cycle (see also Fig. 1). Images were adapted with permission from the Journal of Cell Science (Kölsch et al., 2010) and Molecular Biology of the Cell (Windoffer et al., 2004). Nucleation: Newly appearing particles that are generated in proximity to the plasma membrane (to the right) are encircled. Elongation: An elongating particle is marked by an arrow. Integration: The labeled particles (corresponding particles are color-coded in successive frames) move toward the nucleus, fuse with each other, and integrate into the peripheral keratin network. Bundling: Inward-moving filaments fuse laterally and bundle (one example is marked by an arrow). Disassembly: The demarcated filament bundle disappears gradually without filament fragmentation. Bars, 2 µm.

Figure 3.

Keratin network dynamics in three different situations. (A) Approaching epithelial cells, e.g., upon wound closure: The motile cells require a dynamic cytoskeleton. This is supported by the keratin cycle, which allows rapid turnover and restructuring of the peripheral network using focal adhesion–dependent guidance cues, whereas the perinuclear network remains comparatively static. ecm, extracellular matrix; fa, focal adhesion; n, nucleus. (B) Differentiated static epithelium: Upon stable contact formation with neighboring epithelial cells through tight junctions (tj), adherens junctions (aj), and desmosomes (des), and with the extracellular matrix of the basement membrane through hemidesmosomes (hdes), the keratin network matures into topologically restricted thick bundles with very little keratin cycling. (C) Invasion of epithelial cell into connective tissue: Cells lose contact with each other and reduce stable hemidesmosomal adhesion coincident with up-regulation of keratin cycling in the leading edge for network remodeling.