Chapter 12 : Signaling for Phagocytosis

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Phagocytes ingest a variety of particles, cells, and microbes by use of actin-rich, contractile extensions of plasma membrane that close into intracellular membranous organelles called phagosomes. Signaling for phagocytosis begins when cell surface receptors engage particle-bound molecular ligands. The distinct component activities localize to subregions of forming phagosomes and may be coordinated by membrane-associated proteins and phospholipids that diffuse in the plane of the membrane bilayer. Different receptors use distinct mechanisms for regulating the actin cytoskeleton and the movements of membrane, producing a variety of morphologies for forming phagosomes. Some elements of phagocytic signaling are both constructive and interpretive. This chapter emphasizes the constructive signals. The cytosolic signaling proteins bind to the receptors or associated proteins, and a complex aggregate assembles around the receptor by diffusion and trapping. Secondary signals include the enzymatic modification of phospholipids and other membrane-associated proteins that in turn organize the cytoplasmic movements of phagocytosis. The underlying mechanism of phagocytosis appears to depend less on localized extension of the plasma membrane and more on controlled invagination of the cell surface by actin-myosin contractile activities. The morphogenesis of phagosomes suggests that actinmyosin-like contractility is essential to phagocytosis. The chapter reviews the signals for various different receptor-mediated phagocytic processes. The patterns of GTPase activities and the corresponding patterns of movement for actin, myosin, and membranes may be coordinated by patterns of membrane lipids in the inner leaflet of the inner membrane of the phagocytic cup that appear and disappear through the course of phagocytosis.

Citation: Swanson J. 2009. Signaling for Phagocytosis, p 195-208. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch12
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Image of FIGURE 1

Different morphologies of phagosome formation. Phagocyte membranes (black lines) and actin filaments (gray lines) envelop particles (gray ovals) in distinct patterns. (Extended) Typical of Fc receptor-mediated phagocytosis, actin-rich pseudopodia form a closely adherent, cup-shaped extension around a particle surface. (Sunken) Particles opsonized with C3bi form cytoplasmic indentations of the cell surface as they are drawn into the cell. Actin is organized into discrete, punctate structures, possibly at the base of actin-rich cell protrusions called ruffles. (Coiled) The bacterium is sometimes internalized into coil-shaped phagosomes which form by sheet-like pseudopod that rolls up around the bacterium. The mechanism by which these structures close into phagosomes is not known. (Macropinocytotic) Particles stimulate ruffle formation in nearby regions of the cell surface. They are then enclosed into loosely adherent, spacious phagosomes that resemble macropinosomes.

Citation: Swanson J. 2009. Signaling for Phagocytosis, p 195-208. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch12
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Image of FIGURE 2

Coordination by membrane phospholipids and small GTPases of the various stages of phagosome formation. In the diagrams on the left, thick arrows mark the progression of phospholipid modifications during FcR-mediated phagocytosis, thin solid lines indicate GTPase activation (arrows) or inhibition (cross-bars) by phosphoinositides, and thin broken lines indicate general effector activities of GTPases or other proteins regulated by lipids. Diagrams on the right indicate the morphological stages of phagocytosis and the regions of the forming phagosome in which distinct stages of signaling occur. (A) In the earliest signaling (stage 1), FcRs activate Cdc42, ARF6, and Rac1, which in turn facilitate synthesis of PtdIns(4,5)P (thick black arrows) and activities that promote actin polymerization. Stage 1 activities predominate early during phagocytosis and persist at the distal margin of the phagocytic cup. (B) The accumulation of PtdIns(3,4,5)P and PtdIns(3,4)P in the phagocytic cup initiates stage 2 activities. Cdc42 and ARF6 are inactivated, ARF1 and Rac2 are activated, and Rac1 remains active. These activities, together with those activated by diacylglycerol [DAG; generated from PtdIns(4,5)P], stimulate actin depolymerization, contraction, and the fusion of vesicles with the phagocytic cup. Stage 2 activities are blocked by inhibitors of PI3K. (C) In stage 3, depletion of PtdIns(4,5)P, accumulation of DAG, PtdIns(3,4,5)P, and PtdIns(3,4)P, and the additional generation of PtdIns(3)P lead to deactivation of Rac1 and generation of ROS by NOX2.

Citation: Swanson J. 2009. Signaling for Phagocytosis, p 195-208. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch12
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