Intermediate Filaments in Cellular Mechanoresponsiveness: Mediating Cytoskeletal Crosstalk From Membrane to Nucleus and Back

Abstract

The mammalian cytoskeleton forms a mechanical continuum that spans across the cell, connecting the cell surface to the nucleus via transmembrane protein complexes in the plasma and nuclear membranes. It transmits extracellular forces to the cell interior, providing mechanical cues that influence cellular decisions, but also actively generates intracellular forces, enabling the cell to probe and remodel its tissue microenvironment. Cells adapt their gene expression profile and morphology to external cues provided by the matrix and adjacent cells as well as to cell-intrinsic changes in cytoplasmic and nuclear volume. The cytoskeleton is a complex filamentous network of three interpenetrating structural proteins: actin, microtubules, and intermediate filaments. Traditionally the actin cytoskeleton is considered the main contributor to mechanosensitivity. This view is now shifting owing to the mounting evidence that the three cytoskeletal filaments have interdependent functions due to cytoskeletal crosstalk, with intermediate filaments taking a central role. In this Mini Review we discuss how cytoskeletal crosstalk confers mechanosensitivity to cells and tissues, with a particular focus on the role of intermediate filaments. We propose a view of the cytoskeleton as a composite structure, in which cytoskeletal crosstalk regulates the local stability and organization of all three filament families at the sub-cellular scale, cytoskeletal mechanics at the cellular scale, and cell adaptation to external cues at the tissue scale.

Keywords: actin; cytoskeleton; keratin; mechanobiology; microtubules; migration; vimentin.

FIGURE 1

Cytoskeletal crosstalk between intermediate filaments (IFs), actin filaments (AFs) and microtubules (MTs) contributes to mechanosensing: (A) at the cell surface: mechanical signals emerging from the matrix (A1) or from neighboring cells (A2); (B) in the propagation of mechanical signals across the cell cytoplasm and (C) up to the cell nucleus. (A1) At cell-matrix adhesions, actin/vimentin crosstalk regulates focal adhesion turnover, which results in dissipation of local stresses. Fluorescence image from (Gregor et al., 2014) shows the intimate spatial relation between vimentin (vm), plectin and vinculin, orchestrating focal adhesion turnover; scale bar is 10 µm. (A2) At cell-cell adhesions, actin/intermediate filament crosstalk is activated upon tensile (pulling) forces and participates in the regulation of cellular prestress. (B) In the dense cytoplasm, mechanical forces are transmitted through all three cytoskeletal networks. The intermediate filament network affects the (de)polymerization rates of the other two networks, and the three networks co-align. Fluorescence image from (Vohnoutka et al., 2019) demonstrates the dense organization of vimentin, microtubules (MT) and actin. Vimentin spans from membrane sites to the nucleus (DAPI) and forms a cage surrounding the nucleus. Scale bar is 50 µm. (C) At the nucleus, forces are transmitted between the cytoskeleton and chromatin through LINC complexes, affecting nuclear shape and heterochromatin density, while intermediate filaments protect the nucleus from large deformations. Fluorescence image from (Feliksiak et al., 2020) shows microtubules and vimentin around the nucleus (DAPI); scale bar = 15 µm. Areas marked by A-B-C demonstrate the tight association of vimentin with nuclear grooves.