Diacylglycerol Kinases Terminate Diacylglycerol Signaling during the Respiratory Burst Leading to Heterogeneous Phagosomal NADPH Oxidase Activation

Schlam, Daniel; Bohdanowicz, Michal; Chatilialoglu, Alexandros; Steinberg, Benjamin E.; Ueyama, Takeshi; Du, Guangwei; Grinstein, Sergio; Fairn, Gregory D.

doi:10.1074/jbc.m113.457606

Cited by 35 publications

(22 citation statements)

References 49 publications

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“…DAG pools in all tissues are tightly regulated since these glycerolipids serve multiple critical roles. These roles include: i) precursors for structural glycerophospholipids [7], ii) precursors for triacylglycerols (TAG) and monoacylglycerols (MAG), including the endocannabinoid 2-arachidonyl-glycerol [8–10], iii) mediators of signal transduction via activation of protein kinase C (PKC), protein kinase D (PKD), Ca(2+)/calmodulin-dependent protein kinase (PKCaMII), RasGRP1/Ras/Erk MAPK, chimaerins, and munc13 proteins that regulate neurotransmitter release [11–15], iv) regulation of immunological synapse function [16] and respiratory burst in immune cells like microglia [17]; v) required in the Golgi for transport carrier biogenesis [18]; vi) nuclear signal transduction [19], and vii) structural roles in the endoplasmic reticulum and nuclear envelope [20–21]. …”

Section: Introductionmentioning

confidence: 99%

Targeted Lipidomics of Fontal Cortex and Plasma Diacylglycerols (DAG) in Mild Cognitive Impairment and Alzheimer’s Disease: Validation of DAG Accumulation Early in the Pathophysiology of Alzheimer’s Disease

Wood

Medicherla

Sheikh

et al. 2015

JAD

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Previous studies have demonstrated augmented levels of diacylglycerols (DAG) in the frontal cortex and plasma of Alzheimer’s disease (AD) patients. We extended these findings from non-targeted liopidomics studies to design a lipidomics platform to interrogate DAGs and monoacylglycerols (MAG) in the frontal cortex and plasma of MCI subjects. Control subjects included both aged normal controls and controls with normal cognition, but AD pathology at autopsy, individuals termed non-demented AD neuropathology (NDAN). DAGs with saturated, unsaturated, and polyunsaturated fatty acid substituents were found to be elevated in MCI frontal cortex and plasma. Tandem mass spectrometry of the DAGs did not reveal any differences in the distributions of the fatty acid substitutions between MCI and control subjects. While triacylglycerols were not altered in MCI subjects there were increases in monoacylglycerol levels both in the frontal cortex and plasma. In toto, increased levels of DAGs and MAGs appear to occur early in AD pathophysiology and require both further validation in a larger patient cohort and elucidation of the lipidomics alteration(s) that lead to the accumulation of DAGs in MCI subjects.

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Section: Introductionmentioning

confidence: 99%

Targeted Lipidomics of Fontal Cortex and Plasma Diacylglycerols (DAG) in Mild Cognitive Impairment and Alzheimer’s Disease: Validation of DAG Accumulation Early in the Pathophysiology of Alzheimer’s Disease

Wood

Medicherla

Sheikh

et al. 2015

JAD

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“…These modular domains are genetically encoded proteins that are often expressed as fusions with GFP or mCherry. This type of probe has proven very useful for the analysis of not only the intracellular localization of lipids but also the dynamic changes in these lipids in response to stimuli (Várnai and Balla, 2006;Schlam et al, 2013;Steinberg et al, 2014). These lipidbinding domains are produced in the cytosol and translocate to membranes where the ligands are located.…”

Section: Domains Of Genetically Encoded Proteinsmentioning

confidence: 99%

Molecular probes to visualize the location, organization and dynamics of lipids

Maekawa

Fairn

2014

Journal of Cell Science

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Cellular lipids play crucial roles in the cell, including in energy storage, the formation of cellular membranes, and in signaling and vesicular trafficking. To understand the functions and characteristics of lipids within cells, various methods to image lipids have been established. In this Commentary, we discuss the four main types of molecular probes that have significantly contributed to our understanding of the cell biology of lipids. In particular, genetically encoded biosensors and antibodies will be discussed, and how they have been used extensively with traditional light and electron microscopy to determine the subcellular localization of lipids and their spatial and temporal regulation. We highlight some of the recent studies that have investigated the distribution of lipids and their ability to cluster using super-resolution and electron microscopy. We also examine methods for analyzing the movement and dynamics of lipids, including single-particle tracking (SPT), fluorescence recovery after photobleaching (FRAP) and fluorescence correlation spectroscopy (FCS). Although the combination of these lipid probes and the various microscopic techniques is very powerful, we also point out several potential caveats and limitations. Finally, we discuss the need for new probes for a variety of phospholipids and cholesterol.

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“…1B. Notably, NBT staining also highlights the established, normal heterogeneity in superoxide production, apparent between cells and among phagosomes within individual cells, which has been documented in neutrophils and macrophages by us and others [35,47].…”

Section: Differential Activation Of Neutrophils By Opsonized and Unopmentioning

confidence: 59%

“…1B), demonstrating local superoxide accumulation. Thus, although some heterogeneity of NBT staining intensity at the level of individual phagosomes is expected [35,47], a distinct NBT-negative PMN subset was not detected. Despite ROS production, the lifespan of these PMNs was indistinguishable from neutrophils that were infected with unopsonized bacteria (Figs.…”

Section: Discussionmentioning

confidence: 90%

Francisella novicida inhibits spontaneous apoptosis and extends human neutrophil lifespan

Kinkead

Fayram

Allen

2017

Journal of Leukocyte Biology

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is a Gram-negative bacterium that is closely related to the highly virulent facultative intracellular pathogen, Data published by us and others demonstrate that virulence correlates directly with its ability to impair constitutive apoptosis and extend human neutrophil lifespan. In contrast, is attenuated in humans, and the mechanisms that account for this are incompletely defined. Our published data demonstrate that binds natural IgG that is present in normal human serum, which in turn, elicits NADPH oxidase activation that does not occur in response to As it is established that phagocytosis and oxidant production markedly accelerate neutrophil death, we predicted that may influence the neutrophil lifespan in an opsonin-dependent manner. To test this hypothesis, we quantified bacterial uptake, phosphatidylserine (PS) externalization, and changes in nuclear morphology, as well as the kinetics of procaspase-3, -8, and -9 processing and activation. To our surprise, we discovered that not only failed to accelerate neutrophil death but also diminished and delayed apoptosis in a dose-dependent, but opsonin-independent, manner. In keeping with this, studies of conditioned media (CM) showed that neutrophil longevity could be uncoupled from phagocytosis and that stimulated neutrophil secretion of CXCL8. Taken together, the results of this study reveal shared and unique aspects of the mechanisms used by species to manipulate neutrophil lifespan and as such, advance understanding of cell death regulation during infection.

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Diacylglycerol Kinases Terminate Diacylglycerol Signaling during the Respiratory Burst Leading to Heterogeneous Phagosomal NADPH Oxidase Activation

Cited by 35 publications

References 49 publications

Targeted Lipidomics of Fontal Cortex and Plasma Diacylglycerols (DAG) in Mild Cognitive Impairment and Alzheimer’s Disease: Validation of DAG Accumulation Early in the Pathophysiology of Alzheimer’s Disease

Targeted Lipidomics of Fontal Cortex and Plasma Diacylglycerols (DAG) in Mild Cognitive Impairment and Alzheimer’s Disease: Validation of DAG Accumulation Early in the Pathophysiology of Alzheimer’s Disease

Molecular probes to visualize the location, organization and dynamics of lipids

Francisella novicida inhibits spontaneous apoptosis and extends human neutrophil lifespan

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