Chapter 27 : Molecular Mechanisms of Phagosome Formation

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Phagocytosis culminates with the entrapment of the target particles within large vacuoles called phagosomes. Because of the multiplicity of phagocytic receptors, it is becoming apparent that a variety of different signaling cascades can be activated during the process. However, several aspects of phagocytosis appear to be conserved, distinguishing it from other mechanisms of cellular uptake such as endocytosis and macropinocytosis. First, phagocytosis can accommodate a wide variety of particle sizes, from hundreds of nanometers to tens of micrometers ( ), as well as complex particle morphologies ( ). Second, phagocytosis requires the progressive engagement of phagocyte surface receptors around the entire particle ( ). This ratchet mechanism has been described as the “zipper” model, which contrasts with the limited number of independent receptors that need to be activated by soluble ligands to trigger macropinocytosis ( ). Third, phagocytosis is an active mechanism that involves local remodeling of the actin cytoskeleton, which drives the deformation of the plasma membrane and the progression of the receptor/ligand “ratchet” around the particle ( ). In addition, as the actin cytoskeleton is tightly associated with the plasma membrane, signaling mediated by phospholipids appears to be a common feature of phagocytosis. Phosphoinositides in particular play a critical role, as phosphatidylinositol 3-kinase (PI3K) is seemingly involved in virtually all known phagocytic systems ( ). These different features impose a temporal progression of the phagosome formation, which can be described by the following sequence of events: (i) binding of the ligand to surface receptors; (ii) activation of receptor-mediated signaling cascades; (iii) remodeling of the actin cytoskeleton; (iv) progressive engagement of additional receptors around the particle; and (v) membrane fusion, leading to the closure of the phagosome ( Fig. 1 ). Yet despite these conserved traits, one cannot fully appreciate the molecular mechanisms involved in phagosome formation without taking into account the diversity of phagocytic receptors and the variety of signaling cascades they induce individually and cooperatively. Thus, here, we chose to focus on some of the best-characterized receptors and signaling pathways in order to give an overview of the many roads that lead to phagosome formation, whereas phagosome maturation and subsequent responses will be described elsewhere.

Citation: Jaumouillé V, Grinstein S. 2017. Molecular Mechanisms of Phagosome Formation, p 507-526. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0013-2015
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Figure 1

Temporal sequence of particle uptake by phagocytosis. Particle surface molecules are engaged by phagocyte receptors. Actin-driven membrane dynamics facilitate the detection of surrounding particles. Engagement and activation of the receptor lead to the induction of signaling cascades that elicit actin reorganization. Actin polymerization progresses around the particle, accompanied by further engagement of receptors. Actin clearance and focal exocytosis at the base of the cup facilitate particle engulfment. Once the particle is fully surrounded, membrane fusion at the rims of the cup seals the phagosome and separates it from the plasma membrane.

Citation: Jaumouillé V, Grinstein S. 2017. Molecular Mechanisms of Phagosome Formation, p 507-526. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0013-2015
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Figure 2

Signaling cascades leading to actin reorganization during FcγR-mediated phagocytosis. Engagement and aggregation of FcγRs activate tyrosine kinases (yellow), which recruit multiple adaptor proteins (green). The FcγR signaling complex activates lipid modification enzymes (orange), GEFs (pink), actin modulators (navy blue), and Rho GTPases (purple). By activating nucleation-promoting factors (brown), they stimulate the activity of the Arp2/3 complex (red), which nucleates actin polymerization into a branched network. Abbreviations: PIP, phosphatidylinositol 3,4,5-trisphosphate; PLD, phospholipase D.

Citation: Jaumouillé V, Grinstein S. 2017. Molecular Mechanisms of Phagosome Formation, p 507-526. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0013-2015
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Figure 3

Molecular mechanism of fungi phagocytosis by Dectin-1. Engagement of Dectin-1 leads to the phosphorylation of its hemi-ITAM by SFKs and the recruitment of Syk. Activation of these kinases is facilitated by the exclusion of the tyrosine phosphatases CD45 and CD148 from the phagocytic cup. The combined action of SFKs, Syk, PI3K, and PKC lead to the activation of the small GTPases Rac and Cdc42, which activate Arp2/3-driven actin polymerization.

Citation: Jaumouillé V, Grinstein S. 2017. Molecular Mechanisms of Phagosome Formation, p 507-526. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0013-2015
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Figure 4

Actin reorganization during complement-mediated phagocytosis by the integrin αβ (CR3). Rap-1-mediated inside-out activation of CR3 via its association with talin can be induced by various receptors, including TLRs, G protein-coupled receptors (GPCRs), and Fc receptors. Engagement of CR3 leads to the activation of PI3K and the small GTPases RhoA and RhoG. RhoA activates the actin nucleator of the formin family mDia1, which stimulates actin polymerization into a linear network, whereas the serine/threonine kinase ROCK activates myosin II, which favors the recruitment of the Arp2/3 complex, leading to the polymerization of a branched actin network.

Citation: Jaumouillé V, Grinstein S. 2017. Molecular Mechanisms of Phagosome Formation, p 507-526. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0013-2015
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Figure 5

Signaling events in phagocytosis of apoptotic bodies mediated by TIM-4. TIM-4 and integrins cooperate to take up apoptotic bodies. SFK, FAK, and PI3K activities lead to the stimulation of Vav3, a GEF for RhoA and Rac, which activate the actin nucleators mDia and Arp2/3, respectively. oxPS; oxidized phosphatidylserine.

Citation: Jaumouillé V, Grinstein S. 2017. Molecular Mechanisms of Phagosome Formation, p 507-526. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0013-2015
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Table 1

Phagocytic receptors and their specific ligands

Citation: Jaumouillé V, Grinstein S. 2017. Molecular Mechanisms of Phagosome Formation, p 507-526. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0013-2015

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