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Biochemical and mechanical regulation of actin dynamics

Abstract

Polymerization of actin filaments against membranes produces force for numerous cellular processes, such as migration, morphogenesis, endocytosis, phagocytosis and organelle dynamics. Consequently, aberrant actin cytoskeleton dynamics are linked to various diseases, including cancer, as well as immunological and neurological disorders. Understanding how actin filaments generate forces in cells, how force production is regulated by the interplay between actin-binding proteins and how the actin-regulatory machinery responds to mechanical load are at the heart of many cellular, developmental and pathological processes. During the past few years, our understanding of the mechanisms controlling actin filament assembly and disassembly has evolved substantially. It has also become evident that the activities of key actin-binding proteins are not regulated solely by biochemical signalling pathways, as mechanical regulation is critical for these proteins. Indeed, the architecture and dynamics of the actin cytoskeleton are directly tuned by mechanical load. Here we discuss the general mechanisms by which key actin regulators, often in synergy with each other, control actin filament assembly, disassembly, and monomer recycling. By using an updated view of actin dynamics as a framework, we discuss how the mechanics and geometry of actin networks control actin-binding proteins, and how this translates into force production in endocytosis and mesenchymal cell migration.

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Fig. 1: Principles of actin dynamics.
Fig. 2: Nucleation and assembly of branched and linear filament structures.
Fig. 3: Interplay between actin filament nucleation and assembly pathways.
Fig. 4: Interplay between actin-binding proteins in filament network disassembly.
Fig. 5: Applying a mechanical load to actin networks affects actin dynamics in many ways.
Fig. 6: Mechanics of Arp2/3-nucleated actin filament networks in cell migration and endocytosis.
Fig. 7: Molecular explanation for branched network mechano-adaptation.

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Glossary

Barbed end

The rapidly growing end of an actin filament, as opposed to the pointed end. In cells, actin filament barbed ends typically face the plasma membrane or cellular organelles. Polymerization of actin filaments at their barbed end generates a pushing force.

Pointed end

The slowly growing end of an actin filament. For pure actin in the steady state, actin filament disassembly predominantly occurs at the filament pointed ends.

Treadmilling

Phenomenon originating from simultaneous elongation of an actin filament at its barbed end and depolymerization from its pointed end. In the steady state, the polymerization and depolymerization rates are equal, and thus the filament has a constant length, while monomers flow through the filament from barbed ends to pointed ends.

Mechanosensing

The ability of a cell to sense its mechanical environment. The information from the mechanical environment is often translated into biochemical signals, which can control multiple processes of the cell.

Fascin

An actin-bundling protein that organizes filaments with similar orientations in dense arrays. Fascin 1 is the main bundling protein in filopodial structures.

CARMIL

Family of proteins involved in migration and morphogenesis of animal cells. CARMILs interact with capping protein (CP) at the leading edge of motile cells and control the association of CP with and the dissociation of CP from actin filament barbed ends.

Stress fibres

Contractile actomyosin bundles of a non-muscle cell. Stress fibres are typically associated from their ends with extracellular matrix through focal adhesions, and are thus important for cell adhesion, morphogenesis and mechanosensing.

WAVE regulatory complex

(WRC). A pentameric complex that contains the nucleation-promoting factor WAVE. Upon activation by Rac1, WAVE can bind and activate the Arp2/3 complex to form branch networks implicated in cell protrusion.

Chiral processes

An object, or a process, is chiral if it is distinguishable from its mirror image. Chiral processes may lead to asymmetric distributions of organelles and the appearance of concentration gradients at the cellular level or tissue level, and possibly the emergence of left–right asymmetry at the organism level.

LIM domain proteins

A large family of proteins that contain one or several LIM domains, and whose localization to actin cytoskeleton structures such as stress fibres is enhanced upon mechanical stress application. Most well-known proteins are the members from the zyxin, paxillin and FHL subfamily.

α-Catenin

Protein involved in the complex regulation of cell–cell adhesion, mainly by acting as a mechanosensitive adaptor protein, linking the actin cytoskeleton to transmembrane proteins called ‘cadherins’.

Turgor pressure

Force, originating from the osmotic pressure inside the cell, which pushes the plasma membrane against the cell wall in plants, yeasts and bacteria.

ENTH/ANTH domain proteins

A family of actin- and membrane-binding proteins which contribute to endocytosis. These proteins can link elongating actin filaments to the endocytic invagination.

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Lappalainen, P., Kotila, T., Jégou, A. et al. Biochemical and mechanical regulation of actin dynamics. Nat Rev Mol Cell Biol (2022). https://doi.org/10.1038/s41580-022-00508-4

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