Calcium-binding protein EhCaBP3 is recruited to the phagocytic complex of Entamoeba histolytica by interacting with Arp2/3 complex subunit 2

Phagocytosis is a remarkably complex and versatile process: it contributes to innate immunity through the ingestion and elimination of pathogens, while also being central to tissue homeostasis and remodeling by clearing effete cells. The ability of phagocytes to perform such diverse functions rests, in large part, on their vast repertoire of receptors. In this review, we address the various receptor types, their mobility in the plane of the membrane, and two modes of receptor crosstalk: priming and synergy. A major section is devoted to the actin cytoskeleton, which not only governs receptor mobility and clustering but also is instrumental in particle engulfment. Four stages of the actin remodeling process are identified and discussed: (i) the 'resting' stage that precedes receptor engagement, (ii) the disruption of the cortical actin prior to formation of the phagocytic cup, (iii) the actin polymerization that propels pseudopod extension, and (iv) the termination of polymerization and removal of preassembled actin that are required for focal delivery of endomembranes and phagosomal sealing. These topics are viewed in the larger context of the differentiation and polarization of the phagocytic cells.

Immune cells kill microbes by engulfing them in a membrane-enclosed compartment, the phagosome. Phagocytosis is initiated when foreign particles bind to receptors on the membrane of phagocytes. The best-studied phagocytic receptors, those for Igs (FcgammaR) and for complement proteins (CR), activate PLC and PLD, resulting in the intracellular production of the Ca(2+)-mobilizing second messengers InsP3 and S1P, respectively. The ensuing release of Ca(2+) from the ER activates SOCE channels in the plasma and/or phagosomal membrane, leading to sustained or oscillatory elevations in cytosolic Ca(2+) concentration. Cytosolic Ca(2+) elevations are required for efficient ingestion of foreign particles by some, but not all, phagocytic receptors and stringently control the subsequent steps involved in the maturation of phagosomes. Ca(2+) is required for the solubilization of the actin meshwork that surrounds nascent phagosomes, for the fusion of phagosomes with granules containing lytic enzymes, and for the assembly and activation of the superoxide-generating NADPH oxidase complex. Furthermore, Ca(2+) entry only occurs at physiological voltages and therefore, requires the activity of proton channels that counteract the depolarizing action of the phagocytic oxidase. The molecules that mediate Ca(2+) ion flux across the phagosomal membrane are still unknown but likely include the ubiquitous SOCE channels and possibly other types of Ca(2+) channels such as LGCC and VGCC. Understanding the molecular basis of the Ca(2+) signals that control phagocytosis might provide new, therapeutic tools against pathogens that subvert phagocytic killing.

The GTPase dynamin is essential for CME (clathrin-mediated endocytosis), but its exact function and mechanism of action have been controversial. Here, we review findings that have led to the current models for dynamin function, either as a mechanochemical enzyme driving membrane fission or as a regulatory GTPase monitoring rate-limiting steps in CME. However, these models are not mutually exclusive and subsequent studies have provided evidence for both dynamin functions. Recent evidence derived from divergent in vivo and in vitro approaches suggests that dynamin plays a dual role in CME, functioning at early stages as a fidelity monitor to regulate clathrin-coated pit maturation and at later stages to directly catalyse membrane fission and clathrin-coated vesicle formation.