Intracellular Movements and Changes in Cell Shape Are Driven by Actin Polymerization

By manipulating actin polymerization and depolymerization, the cell can create forces that produce several types of movement. As noted previously and described in detail later, actin polymerization at the leading edge of a moving cell is critical to cell migration. Here, we consider other examples of cell movement that most likely result from actin polymerization—one concerning infection and the other blood clotting.

Most infections are spread by bacteria or viruses that are liberated when an infected cell lyses. However, some bacteria and viruses escape from a cell on the end of a polymerizing actin filament. Examples include Listeria monocytogenes, a bacterium that can be transmitted from a pregnant woman to the fetus, and vaccinia, a virus related to the smallpox virus. When such organisms infect mammalian cells, they move through the cytosol at rates approaching 11 ^m/min. Fluorescence microscopy revealed that a meshwork of short actin filaments follows a moving bacterium or virus like the plume of a rocket exhaust (Figure 19-13). These observations suggested that actin generates the force necessary for movement.

The first hints about how actin mediates bacterial movement were provided by a microinjection experiment in which fluorescence-labeled G-actin was injected into Listeria-infected cells. In the microscope, the labeled monomers could be seen incorporating into the tail-like meshwork at the end

▲ EXPERIMENTAL FIGURE 19-13 Fluorescence microscopy implicates actin in movement of Listeria in infected fibroblasts.

Bacteria (red) are stained with an antibody specific for a bacterial membrane protein that binds cellular profilin and is essential for infectivity and motility. Behind each bacterium is a "tail" of actin (green) stained with fluorescent phalloidin. Numerous bacterial cells move independently within the cytosol of an infected mammalian cell. Infection is transmitted to other cells when a spike of cell membrane, generated by a bacterium, protrudes into a neighboring cell and is engulfed by a phagocytotic event. [Courtesy of J. Theriot and T Mitchison.]

▲ EXPERIMENTAL FIGURE 19-14 Platelets change shape during blood clotting. Resting cells have a discoid shape (left). When exposed to clotting agents, the cells settle on the substratum, extend numerous filopodia (center), and then spread out (right). The changes in morphology result from complex rearrangements of the actin cytoskeleton, which is cross-linked to the plasma membrane. [Courtesy of J. White.]

nearest the bacterium, with a simultaneous loss of actin throughout the tail. This result showed that actin polymerizes into filaments at the base of the bacterium and suggested that, as the tail-like meshwork assembles, it pushes the bacterium ahead. Findings from studies with mutant bacteria indicate that the interaction of cellular Arp 2/3 with a bacterial membrane protein promotes actin polymerization at the end of the tail nearest the bacterium. Recent studies have detected rocket tails trailing common cytoplasmic vesicles such as endosomes. Such observations suggest that actin polymerization may underlie the movement of endosomes in the cytoplasm.

During blood clotting, complicated rearrangements of the cytoskeleton in activated platelets dramatically change the cell shape and promote clot formation (Figure 19-14). The cytoskeleton of an unactivated platelet consists of a rim of microtubules (the marginal band), a membrane skeleton, and a cytosolic actin network. The membrane skeleton in

▲ FIGURE 19-15 Cross-linkage of actin filament networks to the platelet plasma membrane. In platelets, a three-dimensional network of actin filaments is attached to the integral membrane glycoprotein complex Gp1b-IX by filamin. Gp1b-IX also binds to proteins in a blood clot outside the platelet. Platelets also possess a two-dimensional cortical network of actin and spectrin similar to that underlying the erythrocyte membrane (see Figure 5-31). (b) This composite picture of the actin cytoskeleton in a resting platelet shows the different arrangements of microfilaments. Beneath the plasma membrane (1) lies a two-dimensional network of filaments ( 2|) cross-linked by spectrin. Filamin organizes the filaments into a three-dimensional gel ( 3), forming the cortex of the cell. A lattice of filament bundles (4|) forms adhesions to the underlying substratum. The disk shape of the cell is maintained by a ring of microtubules ( 5) at the cell periphery. [Part (b) courtesy of John Hartwig.]

platelets is somewhat similar to the cortical cytoskeleton in erythrocytes (see Figure 5-31). A critical difference between erythrocytes and platelet cytoskeletons is the presence in the platelet of the second network of actin filaments, which are organized by filamin cross-links into a three-dimensional gel (Figure 19-15). The gel fills the cytosol of a platelet and is anchored by filamin to a glycoprotein complex (Gp1b-IX) in the platelet membrane. Gp1b-IX not only binds filamin but also is the membrane receptor for two blood-clotting proteins. Through Gp1b-IX and an integrin receptor, forces generated during rearrangements of the actin cytoskeleton in platelets can be transmitted to a developing clot. Several examples of similar connections between the cytoskeleton and components of the extracellular matrix are described in Chapter 6.

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