The cell pushes back: The Arp2/3 complex is a key orchestrator of cellular responses to environmental forces

Abstract

The Arp2/3 complex orchestrates the formation of branched actin networks at the interface between the cytoplasm and membranes. Although it is widely appreciated that these networks are useful for scaffolding, creating pushing forces and delineating zones at the membrane interface, it has only recently come to light that branched actin networks are mechanosensitive, giving them special properties. Here, we discuss recent advances in our understanding of how Arp2/3-generated actin networks respond to load forces and thus allow cells to create pushing forces in responsive and tuneable ways to effect cellular processes such as migration, invasion, phagocytosis, adhesion and even nuclear and DNA damage repair.

Keywords: Actin; Arp2/3 complex; Cell migration; Endocytosis; Mechanosensing; Metabolism.

Figure 1

Branched actin networks are load-sensitive and direct membrane dynamics. (A) Branched actin networks are load-sensitive. Scheme shows actin filaments growing at steady state with intermediate force load (middle, grey arrow). An increase in load (left, blue arrow) increases filament density, whereas after a decrease in load (right, red arrow) density decreases and branched filaments proximal to the membrane are preferentially capped (red). The Arp2/3 complex is highlighted in blue. F; Force. Figure adapted from the study by Mueller et al. [16]. (B) Spatially constrained branched actin networks enable endocytic uptake of clathrin-coated pits. Generation of force by the actin assembly shapes the dynamics of plasma membrane. This is especially evident by the manifestations of the actin cytoskeleton during clathrin-mediated endocytosis (CME). Actin is organised as a radial branched array with growing ends facing the base of the pit. During endocytosis, long actin filaments bend between attachment sites in the coat and the base of the endocytic vesicle, and therefore endocytic internalisation depends on elastic energy stored in bent filaments. This is based on the neck of the endocytic vesicle being a flexible spring and generating tension between the plasma membrane and the nascent vesicle. It has been shown that a band of the actin capturing molecule Hip1R near the internal distal end of the vesicle could capture actin filaments and allow load-responsive polymerisation of Arp2/3-induced dendritic networks to oppose the membrane tension forces. Increased membrane tension directs more growing filaments toward the base of the pit increasing actin nucleation and bending locally and therefore increased force production derived from branched actin. Spatially constrained actin filament assembly therefore enables endocytosis [21].

Figure 2

Arp2/3-dependent actin branching at the roots of the responses to environmental forces. There is a bidirectional mechanical communication between cells and their environment. Among the main contributors to cell responses against increased force load are (1) branched actin networks (2) which are generated through Arp2/3-mediated dendritic nucleation. Branched actin networks are key in controlling the tension homeostasis (3) at the cytoskeleton–plasma membrane–ECM axis. Dynamics of branched actin networks are involved in many processes inside the cell and apart from cell–ECM and cell–cell contacts and also influence cell protrusion and motility (a), nucleus dynamics and genetic stability (b) as well as trafficking of organelles such as mitochondria and therefore cellular energetics (c). DSB, double-strand breaks.