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Signal transduction during fc receptor-mediated phagocytosis
- Journal of Leukocyte Biology
"... Abstract: Phagocytosis is the process whereby cells engulf large particles, usually over 0.5 �m in diameter. Phagocytosis is triggered by the interaction of opsonins that cover the particle to be internalized with specific receptors on the surface of the phagocyte. The best-studied phagocytic recept ..."
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Abstract: Phagocytosis is the process whereby cells engulf large particles, usually over 0.5 �m in diameter. Phagocytosis is triggered by the interaction of opsonins that cover the particle to be internalized with specific receptors on the surface of the phagocyte. The best-studied phagocytic receptors include the Fc receptors (FcR) that bind to the Fc portion of immunoglobulins. Cross-linking of FcR on the phagocyte initiates a variety of signals, which lead through the reorganization of the actin cytoskeleton, and membrane remodeling, to the formation of the phagosome. From recent data, it is becoming clear that FcR-mediated phagocytosis occurs as a series of steps that are regulated in a nonlinear manner and that signaling for phagocytosis does not terminate when the phagosome is formed. Several lipid molecules localize around the nascent phagosome and function as initiators of important signaling pathways for the late stages of phagolysosome formation. In addition, the use of particular signaling molecules may change for different receptors and may also vary depending on the activation or differentiation state of the cell. This review focuses on this new information and presents a model of our present understanding of the signal transduction events that regulate phagocytosis
H (2011) Phagosome dynamics during phagocytosis by neutrophils
- J Leukoc Biol
"... The neutrophil is a key player in immunity, and its activi-ties are essential for the resolution of infections. Neu-trophil-pathogen interactions usually trigger a large ar-senal of antimicrobial measures that leads to the highly efficient killing of pathogens. In neutrophils, the phago-cytic proces ..."
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The neutrophil is a key player in immunity, and its activi-ties are essential for the resolution of infections. Neu-trophil-pathogen interactions usually trigger a large ar-senal of antimicrobial measures that leads to the highly efficient killing of pathogens. In neutrophils, the phago-cytic process, including the formation and maturation of the phagosome, is in many respects very different from that in other phagocytes. Although the complex mecha-nisms that coordinate the membrane traffic, oxidative burst, and release of granule contents required for the microbicidal activities of neutrophils are not completely understood, it is evident that they are unique and differ from those in macrophages. Neutrophils exhibit more rapid rates of phagocytosis and higher intensity of oxi-dative respiratory response than do macrophages. The phagosome maturation pathway in macrophages, which is linked to the endocytic pathway, is replaced in neutrophils by the rapid delivery of preformed granules to nonacidic phagosomes. This review describes the plasticity and dynamics of the phagocytic process with a special focus on neutrophil phagosome maturation. J. Leukoc. Biol. 90: 271–284; 2011.
The coordination of signaling during Fc receptor-mediated phagocytosis
- Journal of Leukocyte Biology
"... Abstract: Phagocytosis by macrophages can be initiated by Fc � receptors (FcR) in membranes that bind to Fc regions of immunoglobulin G (IgG). Activated FcR transduce signals to cytoplasm, which regulate the internalization of IgG-coated particles into plasma membrane-derived vacuoles, phagosomes. P ..."
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Abstract: Phagocytosis by macrophages can be initiated by Fc � receptors (FcR) in membranes that bind to Fc regions of immunoglobulin G (IgG). Activated FcR transduce signals to cytoplasm, which regulate the internalization of IgG-coated particles into plasma membrane-derived vacuoles, phagosomes. Particles internalized by phagocytosis are much larger than FcR, which prompts questions of if and how the receptors are coordinated with each other. FcR-mediated signal transduction entails recruitment of proteins from cytoplasm to the receptor, largely via protein phosphorylation. These FcR signaling complexes then activate proteins that regulate actin, myosin, membrane fusion, and the production of reactive oxygen intermediates. Recent fluorescence microscopic studies of phagocytosis in macrophages indicate that signaling by FcR occurs as a sequence of distinct stages, evident in the spatial and temporal patterns of phosphoinositides, protein kinase C, and Rhofamily GTPase activation on forming phagosomes. The coordination of these stages may be regulated by lipids or lipid-anchored proteins, which diffuse away from FcR complexes. Lateral diffusion of FcR-derived signals could integrate FcR-dependent responses over large areas of membrane in the forming phagosome. J. Leukoc. Biol. 76:
Phagocytosis by neutrophils
- Microbes Infect
, 2003
"... Abstract Phagocytosis is central to the microbicidal function of neutrophils. Pathogens are initially engulfed into a plasma membrane-derived vacuole, the phagosome, which proceeds to acquire degradative properties by a complex process termed maturation. In this chapter, we discuss the current know ..."
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Abstract Phagocytosis is central to the microbicidal function of neutrophils. Pathogens are initially engulfed into a plasma membrane-derived vacuole, the phagosome, which proceeds to acquire degradative properties by a complex process termed maturation. In this chapter, we discuss the current knowledge of the molecular mechanisms underlying phagosome formation and maturation in neutrophils.
The nature of the phagosomal membrane: endoplasmic reticulum versus plasmalemma
- J. Leukocyte Biol
, 2005
"... Abstract: For decades, the vacuole that sur-rounds particles engulfed by phagocytosis was be-lieved to originate from the plasma membrane. Conversion of the nascent phagosome into a micro-bicidal organelle was thought to result from the subsequent, orderly fusion of early endosomes, late endosomes, ..."
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Abstract: For decades, the vacuole that sur-rounds particles engulfed by phagocytosis was be-lieved to originate from the plasma membrane. Conversion of the nascent phagosome into a micro-bicidal organelle was thought to result from the subsequent, orderly fusion of early endosomes, late endosomes, and ultimately, lysosomes with the original plasma membrane-derived vacuole. This conventional model has been challenged, if not superseded, by a revolutionary model that regards phagosome formation as resulting from the particle sliding into the endoplasmic reticulum via an open-ing at the base of the phagocytic cup. The merits and implications of these two hypotheses are sum-marized here and analyzed in light of recent
Dynamics of cytoskeletal proteins during Fc receptor-mediated phagocytosis in macrophages
- Mol. Biol. Cell
, 2002
"... Particle ingestion by phagocytosis results from sequential rearrangements of the actin cytoskele-ton and overlying membrane. To assemble a chronology of molecular events during phagosome formation and to examine the contributions of phosphoinositide 3-kinase (PI 3-kinase) to these dynamics, a method ..."
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Cited by 6 (1 self)
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Particle ingestion by phagocytosis results from sequential rearrangements of the actin cytoskele-ton and overlying membrane. To assemble a chronology of molecular events during phagosome formation and to examine the contributions of phosphoinositide 3-kinase (PI 3-kinase) to these dynamics, a method was developed for synchronizing Fc receptor-mediated phagocytosis by murine macrophages. Erythrocytes opsonized with complement component C3bi were bound to macrophages at 37°C, a condition that does not favor particle phagocytosis. Addition of soluble anti-erythrocyte IgG resulted in rapid opsonization of the bound erythrocytes, followed by their immediate internalization via phagocytosis. Cellular content of F-actin, as measured by binding of rhodamine-phalloidin, increased transiently during phagocytosis, and this increase was not diminished by inhibitors of PI 3-kinase. Immunofluorescence localization of myosins in macro-phages fixed at various times during phagocytosis indicated that myosins II and IXb were concentrated in early phagosomes, myosin IC increased later, and myosin V appeared after phagosome closure. Other cytoskeletal proteins showed similar variations in the timing of their appearance in phagosomes. The PI 3-kinase inhibitor wortmannin did not change the dynamics of PI 3-kinase or ezrin localization but prevented the loss of PAK1 from phagosomes. These results suggest that PI 3-kinase deactivates PAK1, and that this may be needed for phagosome closure.
Arf6 and Phosphoinositol-4-Phosphate-5-Kinase Activities Permit Bypass of the Rac1 Requirement for � 1 Integrin–mediated Bacterial Uptake
"... Efficient entry of the bacterium Yersinia pseudotuberculosis into mammalian cells requires the binding of the bacterial invasin protein to �1 integrin receptors and the activation of the small GTPase Rac1. We report here that this Rac1-dependent pathway involves recruitment of phosphoinositol-4-phos ..."
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Efficient entry of the bacterium Yersinia pseudotuberculosis into mammalian cells requires the binding of the bacterial invasin protein to �1 integrin receptors and the activation of the small GTPase Rac1. We report here that this Rac1-dependent pathway involves recruitment of phosphoinositol-4-phosphate-5-kinase (PIP5K) to form phosphoinositol-4,5-bisphosphate (PIP2) at the phagocytic cup. Reducing the concentration of PIP2 in the target cell by using a membrane-targeted PIP2-specific phosphatase lowered bacterial uptake proportionately. PIP2 formation is regulated by Arf6. An Arf6 derivative defective for nucleotide binding (Arf6N122I) interfered with uptake and decreased the level of PIP2 around extracellular bacteria bound to host cells. This reduction in PIP2 occurred in spite of fact that PIP5K appeared to be recruited efficiently to the site of bacterial binding, indicating a role for Arf6 in activation of the kinase. The elimination of the Rac1-GTP–bound form from the cell by the introduction of the Y. pseudotuberculosis YopE RhoGAP protein could be bypassed by the overproduction of either PIP5K or Arf6, although the degree of bypass was greater for Arf6 transfectants. These results indicate that both Arf6 and PIP5K are involved in integrin-dependent uptake, and that Arf6 participates in both activation of PIP5K as well as in other events associated with bacterial uptake. Key words: integrin • Rac1 • Arf6 • PIP5K • Yersinia uptake
Dynamin regulates focal exocytosis in phagocytosing macrophages
, 2003
"... Phagocytosis in macrophages is thought to involve insertion of cytoplasmic vesicles at sites of membrane expansion before particle ingestion (“focal ” exocytosis). Capacitance (Cm) measurements of cell surface area were biphasic, with an initial rise indicative of exocytosis followed by a fall upon ..."
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Phagocytosis in macrophages is thought to involve insertion of cytoplasmic vesicles at sites of membrane expansion before particle ingestion (“focal ” exocytosis). Capacitance (Cm) measurements of cell surface area were biphasic, with an initial rise indicative of exocytosis followed by a fall upon phagocytosis. Unlike other types of regulated exocytosis, the Cm rise was insensitive to intracellular Ca 2 � , but was inhibited by guanosine 5�-O-(2-thio)diphosphate. Particle uptake, but not Cm rise, was affected by phosphatidylinositol 3-kinase inhibitors. Inhibition of actin polymerization eliminated the Cm rise, suggesting possible coordination between actin polymerization and focal exocytosis. Introduction of anti-pan-dynamin IgG blocked Cm changes, suggesting that dynamin controls focal exocytosis and thereby phagocytosis. Similarly, recombinant glutathione S-transferase•amphiphysin-SH3 domain, but not a mutated form that cannot bind to dynamin, inhibited both focal exocytosis and phagocytosis. Immunochemical analysis of endogenous dynamin distribution in macrophages revealed a substantial particulate pool, some of
A Cdc42 activation cycle coordinated by PI 3-kinase during Fc receptor-mediated phagocytosis
- Mol Biol Cell
, 2010
"... Fc Receptor (FcR)-mediated phagocytosis by macrophages requires phosphatidylinositol 3-kinase (PI3K) and activation of the Rho-family GTPases Cdc42 and Rac1. Cdc42 is activated at the advancing edge of the phagocytic cup, where actin is concentrated, and is deactivated at the base of the cup. The t ..."
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Fc Receptor (FcR)-mediated phagocytosis by macrophages requires phosphatidylinositol 3-kinase (PI3K) and activation of the Rho-family GTPases Cdc42 and Rac1. Cdc42 is activated at the advancing edge of the phagocytic cup, where actin is concentrated, and is deactivated at the base of the cup. The timing of 3 phosphoinositide (3PI) concentration changes in cup membranes suggests a role for 3PIs in deactivation of Cdc42. This study examined the relationships between PI3K and the patterns of Rho-family GTPase signaling during phagosome formation. Inhibition of PI3K resulted in persistently active Cdc42 and Rac1, but not Rac2, in stalled phagocytic cups. Patterns of 3PIs and Rho-family GTPase activities during phagocytosis of 5- and 2-m-diameter microspheres indicated similar underlying mechanisms despite particle size– dependent sensitivities to PI3K inhibition. Expression of constitutively active Cdc42(G12V) increased 3PI concentrations in plasma membranes and small phagosomes, indicating a role for Cdc42 in PI3K activation. Cdc42(G12V) inhibited phagocytosis at a later stage than inhibition by dominant negative Cdc42(N17). Together, these studies identified a Cdc42 activation cycle organized by PI3K, in which FcR-activated Cdc42 stimulates PI3K and actin polymerization, and the subsequent increase of 3PIs in cup membranes inactivates Cdc42 to allow actin recycling necessary for phagosome formation.
A drosomycin-GFP reporter
- THE JOURNAL OF EXPERIMENTAL BIOLOGY
, 1998
"... Copyright ⓒ 2014 by the The Korean Society for Biochemistry and Molecular Biology This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ..."
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Copyright ⓒ 2014 by the The Korean Society for Biochemistry and Molecular Biology This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License
