From structural resilience to cell specification — Intermediate filaments as regulators of cell fate

Sjöqvist, Marika; Antfolk, Daniel; Rodriguez, Freddy Suarez; Sahlgren, Cecilia

doi:10.1096/fj.202001627r

Cited by 12 publications

(5 citation statements)

References 229 publications

(474 reference statements)

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“…The central role of intermediate filaments in mechanosensitivity may render cell/tissue-specific mechanosensitivity. Moreover, during development, aging or pathology, the composition of the intermediate filament cytoskeleton undergoes major changes ( Redmond and Coulombe 2021 ; Sjöqvist et al, 2021 ). This raises the hypothesis that there may be an “intermediate filament code” that confers cell type-specific mechanosensitive functions.…”

Section: Discussionmentioning

confidence: 99%

“…For instance, different types of epithelial cells express different sets of keratins, mesenchymal cells express vimentin, muscle cells express desmin, and neurons express neurofilaments. Intermediate filaments are hence widely used as markers for differentiation ( Redmond and Coulombe 2021 ; Sjöqvist et al, 2021 ). Herein, we review evidence pointing to the importance of cytoskeletal crosstalk in cellular mechanosensitivity, with a particular focus on the role of intermediate filaments.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Ndiaye

Koenderink

Shemesh

2022

Front. Cell Dev. Biol.

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Ndiaye

Koenderink

Shemesh

2022

Front. Cell Dev. Biol.

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“…Signaling functions of keratin filaments have long been postulated, 72–74 but how such signaling might operate in the context of different keratin isoform mixtures has not been clear. Most keratin signaling proposals rely on knock-out models or filament-disrupting mutants which are confounded by mechanical defects 18,75–83 .…”

Section: Discussionmentioning

confidence: 99%

Keratin isoform shifts modulate motility signals during wound healing

Nanes

Bhatt

Azarova

et al. 2023

Preprint

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Keratin intermediate filaments form strong mechanical scaffolds that confer structural stability to epithelial tissues, but the reason this function requires a protein family with fifty-four isoforms is not understood. During skin wound healing, a shift in keratin isoform expression alters the composition of keratin filaments. How this change modulates cellular function to support epidermal remodeling remains unclear. We report an unexpected effect of keratin isoform variation on kinase signal transduction. Increased expression of wound-associated keratin 6A, but not of steady-state keratin 5, potentiated keratinocyte migration and wound closure without compromising epidermal stability by activating myosin motors. This pathway depended on isoform-specific interaction between intrinsically disordered keratin head domains and non-filamentous vimentin shuttling myosin-activating kinases. These results substantially expand the functional repertoire of intermediate filaments from their canonical role as mechanical scaffolds to include roles as signaling scaffolds that spatiotemporally organize signal transduction cascades depending on isoform composition.

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“…However, in the past years, many additional non-mechanical functions of IFs have been discovered (Patteson et al 2020). IF networks contribute to the functioning of several cellular organelles (Chernoivanenko et al 2015, Styers et al 2004) and regulate signaling pathways that control cell survival, growth, and differentiation (Ridge et al 2022, Sjöqvist et al 2021). Intriguingly, the IF protein family comprises 70 different proteins whose expression pattern is cell-type-specific and changes during development and in disease.…”

Section: Introductionmentioning

confidence: 99%

Reconstitution of cytolinker-mediated crosstalk between actin and vimentin

Petitjean,

Tran,

Goutou

et al. 2023

Preprint

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Cell shape and motility are determined by the cytoskeleton, an interpenetrating network of actin filaments, microtubules, and intermediate filaments. The biophysical properties of each filament type individually have been studied extensively by cell-free reconstitution. By contrast, the interactions between the three cytoskeletal networks are relatively unexplored. They are coupled via crosslinkers of the plakin family such as plectin. These are challenging proteins for reconstitution because of their giant size and multidomain structure. Here we engineer a recombinant actin-vimentin crosslinker protein called ‘ACTIF’ that provides a minimal model system for plectin, recapitulating its modular design with actin-binding and intermediate filament-binding domains separated by a coiled-coil linker for dimerisation. We show by fluorescence and electron microscopy that ACTIF has a high binding affinity for vimentin and actin and creates mixed actin-vimentin bundles. Rheology measurements show that ACTIF-mediated crosslinking strongly stiffens actin-vimentin composites. Finally, we demonstrate the modularity of this approach by creating an ACTIF variant with the intermediate filament binding domain of Adenomatous Polyposis Coli. Our protein engineering approach provides a new cell-free system for the biophysical characterization of intermediate filament-binding crosslinkers and for understanding the mechanical synergy between actin and vimentin in mesenchymal cells.HIGHLIGHTSEngineering of a recombinant actin-vimentin crosslinker called ACTIF with the plectin intermediate filament binding domain (IFBD), calponin homology domains that mediate actin binding, and a coiled-coil linker.ACTIF crosslinks F-actin and vimentin and mediates their co-localizationin vitro.ACTIF has a binding affinity for vimentin that is about 500 times higher than for F-actin.ACTIF forms composite bundles of F-actin and vimentin filaments.Composite F-actin/vimentin networks stiffen upon crosslinking with ACTIF.The design of actin-vimentin crosslinker is modular, as other IFBDs like APCn2 can also be used.

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From structural resilience to cell specification — Intermediate filaments as regulators of cell fate

Cited by 12 publications

References 229 publications

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

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

Keratin isoform shifts modulate motility signals during wound healing

Reconstitution of cytolinker-mediated crosstalk between actin and vimentin

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