The Actin Cytoskeleton General Background

In Figure 8.2 we provide a simplified "global" picture of the main interactions between actin and microtubules with latex bead phagosomes that are important in both phagosome formation and maturation.

Actin filaments, like microtubules (see below) assemble asymmetrically, unlike intermediate filaments which are symmetrically assembled. Actin filaments are very dynamic and undergo permanent assembly and disassembly. The filaments grow faster at one end (the plus end) than at the other (minus end). The actin monomer (globular or G-actin) binds ATP and normally in cells it assembles into filaments in this form. After polymerization, ATP is hydrolyzed to ADP and free phosphate (Pi) that initially stays bound to the filament. The ADP-Pi-bound monomers in the filament lose Pi and the ADP form then depolymerizes at the minus end [20, 21].

The regulation of the actin system is complex since there are well over a hundred actin-binding proteins (ABPs) that mediate different effects on the actin cytoskeleton [22].

Cytoskeleton Binding Proteins

Figure 8.2 Interaction of phagosomes with actin and microtubule cytoskeleton. Early phagosomes interact with mysosin Va at the periphery. This process competes with the association ofthe phagosome with microtubules and subsequent transport to the perinuclear region mediated by dynein. Fusion events controlled by actin during maturation are depicted. Actin can mediate fusion with late endocytic vesicles or block it depending on the age of the phagosome. EE, early endosome; LE/Lys, late endosome-lysosome; MAP, microtubule-associated protein.

Figure 8.2 Interaction of phagosomes with actin and microtubule cytoskeleton. Early phagosomes interact with mysosin Va at the periphery. This process competes with the association ofthe phagosome with microtubules and subsequent transport to the perinuclear region mediated by dynein. Fusion events controlled by actin during maturation are depicted. Actin can mediate fusion with late endocytic vesicles or block it depending on the age of the phagosome. EE, early endosome; LE/Lys, late endosome-lysosome; MAP, microtubule-associated protein.

Most of these ABPs have been extensively analyzed in vitro but their interactions in cells are extremely complex, especially when they interact with membranes, a poorly understood set of processes. Among the different classes of ABP are those that (i) nucleate new filament assembly (e.g., ARP2/3, formins), (ii) block the actin plus (barbed) ends (e.g., capping proteins such as CapZ and gelsolin) or the pointed end (emerin), (iii) crosslink filaments (e.g., a-actinin tropomyosins, fimbrin, villin), (iv) bind lateral F-actin to membranes (e.g., myosin I, calmodulin), (v) bind (sequester or buffer) G-actin (e.g., profilin, thymosins) and (vi) facilitate depolymerization (e.g., cofilin or actin depolymerization factor (ADF)). One of the most difficult aspects of actin biology to address is the nucleation/polymerization of filaments by proteins present on biological membranes. In every known example the filament grows by insertion of actin monomers at the plus ends that are adjacent to the membrane [23]. This is generally a poorly understood process. The latex bead system offers a powerful system to elucidate the mechanisms of this process, as described below.

128 | 8 Phagosome-Cytoskeleton Interactions 8.2.1

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