Phospholipase D—Structure, regulation and function

Exton, John H.

doi:10.1007/bfb0116585

Cited by 213 publications

(202 citation statements)

References 383 publications

(395 reference statements)

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“…These data support the hypothesis that phagocytosis is associated with stimulation of both PLD1 and PLD2. Stimulation of cells with PMA, which is known to activate both PLD1 and PLD2 (18,27), resulted in increased levels of activity in IPs containing PLD1 (170 Ϯ 14% of control), as well as PLD2 (163 Ϯ 7%), supporting the accuracy of this assay ( Fig. 2A).…”

Section: Phagocytic Particles Stimulated Increased Levels Of Pld1 Andsupporting

confidence: 54%

“…This ubiquitous enzyme family is found in viruses, bacteria, fungi, plants, and mammals, and is characterized by a conserved motif, HXKX 4 DX 6 G(G/S), which encompasses the catalytic HKD triad (21)(22)(23). Two mammalian PLDs have been identified and each exhibits complex regulation in vivo and in vitro (18,19,24,25). PLD1 is activated by GTPases of the Rho, Ral, and ADP ribosylation factor families, as well as by protein kinase C (PKC); and phosphatidylinositol-4,5-bisphosphate (PI(4,5)P 2 ) serves as an essential cofactor (24).…”

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confidence: 99%

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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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Section: Phagocytic Particles Stimulated Increased Levels Of Pld1 Andsupporting

confidence: 54%

mentioning

confidence: 99%

Phospholipases D1 and D2 Coordinately Regulate Macrophage Phagocytosis

Barton¹,

Bourgoin²,

Kusner

2004

The Journal of Immunology

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“…The role of PLD in cell growth and oncogenesis is well known because PLD activity is elevated in response to various factors (Exton, 2002). There are many reports demonstrating that, in various tumor cells, the activities and protein expressions of PLD1 or PLD2 are elevated (Foster and Xu, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…PLD has been known to be implicated in various cellular processes (Exton, 2002;Foster and Xu, 2003). A role for PLD in cell proliferation is also suggested from previous reports showing the elevated PLD activity in response to various growth factors and sphingosine 1-phosphate (Liscovitch et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Ewing's sarcoma fusion protein, EWS/Fli-1 and Fli-1 protein induce PLD2 but not PLD1 gene expression by binding to an ETS domain of 5′ promoter

et al. 2006

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It was reported that short interfering RNA (siRNA) of EWS/Fli-1 downregulated phospholipase D (PLD)2 in Ewing's sarcoma (EWS) cell line, suggesting that PLD2 is the target of aberrant transcription factor, EWS/Fli-1. Here, we further investigated the regulation of PLD2 gene expression by EWS/Fli-1 and Fli-1 in another EWS cell line, and also in EWS/Fli-1-or Fli-1-transfected cell line. EWS/Fli-1-or Fli-1-overexpressed cells showed higher PLD2 but not PLD1 protein expression and enhanced cell proliferation as compared to mock transfectant. The treatment of these cells with 1-butanol or siRNA of PLD2 inhibited cell growth, suggesting the pivotal role of PLD in cell growth promotion. PLD2 but not PLD1 mRNA level was also increased in EWS/Fli-1 or Fli-1-transfectants. After determining the transcription initiation points, we cloned the 5 0 promoter of both PLD1 and PLD2 and analysed promoter activities. Results showed that EWS/ Fli-1 and Fli-1 increase PLD2 gene expression by binding to an erythroblast transformation-specific domain (À126 to À120 bp from the transcription initiation site) of PLD2 promoter, which is the minimal and most powerful region. Electrophoresis mobility shift assay using truncated proteins showed that both DNA-binding domain and trans-activating domain were necessary for the enhanced gene expression of PLD2.

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“…Moreover, phospholipase D (PLD) has been recently reported to be actively associated with ATPinduced killing of intracellular mycobacteria by human macrophages (Fairbairn et al ., 2001). Phospholipase D catalyses hydrolysis of the terminal diester bond of phosphatidylcholine as the favourite substrate, to liberate phosphatidic acid (PA) and choline (Liscovithc et al ., 2000;Exton, 2002). A role for PA as a key intracellular signalling molecule has been reported.…”

Section: Introductionmentioning

confidence: 99%

Role of macrophage phospholipase D in natural and CpG-induced antimycobacterial activity

et al. 2003

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SummaryThe present study addresses the differential ability of macrophages to control intracellular growth of nonpathogenic Mycobacterium smegmatis (Msm) and pathogenic M. tuberculosis (MTB). Results reported herein show that 3 h post infection, intracellular Msm , but not MTB, was significantly killed by macrophages. As the role of human macrophage phospholipase D (PLD) in the activation of antimicrobial mechanisms has been documented, we hypothesised the role of such enzyme in antimycobacterial mechanisms. To this aim, macrophage PLD activity was analysed at different times after exposure with either pathogenic MTB or non-pathogenic Msm. Results showed that, starting from 15 min after mycobacterial exposure, MTB did not induce macrophage PLD activity, whereas the environmental non-pathogenic Msm stably increased it. The direct contribution of PLD in intracellular mycobacterial killing was also analysed by inhibiting enzymatic activity with ethanol or calphostin C. Results show that PLD inhibition significantly increases intracellular Msm replication. In order to see whether the innate PLD-mediated antimicrobial mechanisms against MTB are also induced after CpG ODN stimulation, the role of PLD has been analysed in the course of CpG-mediated intracellular MTB killing. CpG DNA increased PLD activity in both uninfected and MTB-infected macrophages, and the inhibition of PLD activity resulted in a significant reduction of CpG-induced MTB killing. Taken together, our data suggest a relationship between host PLD activation and the macrophage ability to control intracellular mycobacterial growth.

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Phospholipase D—Structure, regulation and function

Cited by 213 publications

References 383 publications

Phospholipases D1 and D2 Coordinately Regulate Macrophage Phagocytosis

Phospholipases D1 and D2 Coordinately Regulate Macrophage Phagocytosis

Ewing's sarcoma fusion protein, EWS/Fli-1 and Fli-1 protein induce PLD2 but not PLD1 gene expression by binding to an ETS domain of 5′ promoter

Role of macrophage phospholipase D in natural and CpG-induced antimycobacterial activity

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