Selected lipids activate phagosome actin assembly and maturation resulting in killing of pathogenic mycobacteria

Anes, Elsa; Kühnel, Mark Philipp; Bos, Evelyne; Moniz-Pereira, José; Habermann, Anja; Griffiths, Gareth

doi:10.1038/ncb1036

Cited by 244 publications

(304 citation statements)

References 39 publications

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“…Actin remodeling and phosphatidylinositol 3-kinases are also involved in pseudopod extension during phagocytosis (63). It has recently been shown that arachidonic acid can promote phagosome actin assembly in an in vitro assay (64). We have found that zymosan is internalized in macrophages treated with pyrrolidine, a cPLA 2 ␣ inhibitor that dramatically reduces arachidonic acid release in response to zymosan, suggesting that cPLA 2 ␣ action is not required for phagosome formation (14).…”

Section: Discussionmentioning

confidence: 75%

Cytosolic Phospholipase A2 Translocates to Forming Phagosomes during Phagocytosis of Zymosan in Macrophages

Girotti

Evans

Burke

et al. 2004

Journal of Biological Chemistry

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Resident tissue macrophages mediate early innate immune responses to microbial infection. Cytosolic phospholipase A 2 ␣ (cPLA 2 ␣) is activated in macrophages during phagocytosis of non-opsonized yeast (zymosan) triggering arachidonic acid release and eicosanoid production. cPLA 2 ␣ translocates from cytosol to membrane in response to intracellular calcium concentration ([Ca 2؉ ] i ) increases. Enhanced green fluorescent protein (EGFP)-cPLA 2 ␣ translocated to forming phagosomes, surrounding the zymosan particle by 5 min and completely overlapping with early endosome (Rab5) and plasma membrane (F4/80) markers but only partially overlapping with resident endoplasmic reticulum proteins (GRP78 and cyclooxygenase 2). EGFP-cPLA 2 ␣ also localized to membrane ruffles during phagocytosis. Zymosan induced an initial high amplitude calcium transient that preceded particle uptake followed by a low amplitude sustained calcium increase. Both phases were required for optimal phagocytosis. Extracellular calcium chelation prevented only the sustained phase but allowed a limited number of phagocytic events, which were accompanied by translocation of cPLA 2 ␣ to the phagosome although [Ca 2؉ ] i remained at resting levels. The results demonstrate that cPLA 2 ␣ targets the phagosome membrane, which may serve as a source of arachidonic acid for eicosanoid production.

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Section: Discussionmentioning

confidence: 75%

Cytosolic Phospholipase A2 Translocates to Forming Phagosomes during Phagocytosis of Zymosan in Macrophages

Girotti

Evans

Burke

et al. 2004

Journal of Biological Chemistry

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“…Griffiths and colleagues (73) have recently detected phosphatidic acid (PA), the product of PLD-mediated catalysis and a documented membrane fusogen, on the phagosomal membrane. Our data support the hypothesis that PLD1 is responsible for the generation of phagosomal PA and may directly contribute to the maturation of phagosomes to phagolysosomes via sequential fission and fusion events with vesicles of the endosomal-lysosomal system (59,60).…”

Section: Discussionmentioning

confidence: 99%

Phospholipases D1 and D2 Coordinately Regulate Macrophage Phagocytosis

Barton¹,

Bourgoin²,

Kusner

2004

The Journal of Immunology

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Phagocytosis is a fundamental feature of the innate immune system, required for antimicrobial defense, resolution of inflammation, and tissue remodeling. Furthermore, phagocytosis is coupled to a diverse range of cytotoxic effector mechanisms, including the respiratory burst, secretion of inflammatory mediators and Ag presentation. Phospholipase D (PLD) has been linked to the regulation of phagocytosis and subsequent effector responses, but the identity of the PLD isoform(s) involved and the molecular mechanisms of activation are unknown. We used primary human macrophages and human THP-1 promonocytes to characterize the role of PLD in phagocytosis. Macrophages, THP-1 cells, and other human myelomonocytic cells expressed both PLD1 and PLD2 proteins. Phagocytosis of complement-opsonized zymosan was associated with stimulation of the activity of both PLD1 and PLD2, as demonstrated by a novel immunoprecipitation-in vitro PLD assay. Transfection of dominant-negative PLD1 or PLD2 each inhibited the extent of phagocytosis (by 55–65%), and their combined effects were additive (reduction of 91%). PLD1 and PLD2 exhibited distinct localizations in resting macrophages and those undergoing phagocytosis, and only PLD1 localized to the phagosome membrane. The COS-7 monkey fibroblast cell line, which has been used as a heterologous system for the analysis of receptor-mediated phagocytosis, expressed PLD2 but not PLD1. These data support a model in which macrophage phagocytosis is coordinately regulated by both PLD1 and PLD2, with isoform-specific localization. Human myelomonocytic cell lines accurately model PLD-dependent signal transduction events required for phagocytosis, but the heterologous COS cell system does not.

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“…Signaling pathways exist on membranes of isolated organelles that control actin assembly (Defacque et al, 2000;Eitzen et al, 2002). Recently several reports have also defined a role for lipids in the regulation of actin cytoskeleton remodeling in conjunction with vesicular trafficking Friant et al, 2000Friant et al, , 2001Anes et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Enhanced Membrane Fusion in Sterol-enriched Vacuoles Bypasses the Vrp1p Requirement

Tedrick

Trischuk

Lehner

et al. 2004

MBoC

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Organization of lipids into membrane microdomains is a vital mechanism of protein processing. Here we show that overexpression of ERG6, a gene involved in ergosterol synthesis, elevates sterol levels 1.5-fold on the vacuole membrane and enhances their homotypic fusion. The mechanism of sterol-enhanced fusion is not via more efficient sorting, but instead promotes increased kinetics of fusion subreactions. We initially isolated ERG6 as a suppressor of a vrp1⌬ growth defect selective for vacuole function. VRP1 encodes verprolin, an actin-binding protein that colocalizes to vacuoles. The vrp1⌬ mutant has fragmented vacuoles in vivo and isolated vacuoles do not fuse in vitro, indicative of a Vrp1p requirement for membrane fusion. ERG6 overexpression rescues vrp1⌬ vacuole fusion in a cytosol-dependent manner. Cytosol prepared from the vrp1⌬ strain remains active; therefore, cytosol is not resupplying Vrp1p. Las17p (Vrp1p functional partner) antibodies, which inhibit wild-type vacuole fusion, do not inhibit the fusion of vacuoles from the vrp1⌬-ERG6 overexpression strain. Vacuole-associated actin turnover is decreased in the vrp1⌬ strain, but recovered by ERG6 overexpression linking sterol enrichment to actin remodeling. Therefore, the Vrp1p/Las17p requirement for membrane fusion is bypassed by increased sterols, which promotes actin remodeling as part the membrane fusion mechanism.

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Selected lipids activate phagosome actin assembly and maturation resulting in killing of pathogenic mycobacteria

Cited by 244 publications

References 39 publications

Cytosolic Phospholipase A2 Translocates to Forming Phagosomes during Phagocytosis of Zymosan in Macrophages

Cytosolic Phospholipase A2 Translocates to Forming Phagosomes during Phagocytosis of Zymosan in Macrophages

Phospholipases D1 and D2 Coordinately Regulate Macrophage Phagocytosis

Enhanced Membrane Fusion in Sterol-enriched Vacuoles Bypasses the Vrp1p Requirement

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