Molecular Mechanisms of Phagosome Formation

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 (1, 2), as well as complex particle morphologies (3, 4). Second, phagocytosis requires the progressive engagement of phagocyte surface receptors around the entire particle (5). 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 (6). 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 (7 – 10). 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 (11 – 14). 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.

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