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Nature Reviews. Immunology Sep 2019Tissue macrophages rapidly recognize and engulf apoptotic cells. These events require the display of so-called eat-me signals on the apoptotic cell surface, the most... (Review)
Review
Tissue macrophages rapidly recognize and engulf apoptotic cells. These events require the display of so-called eat-me signals on the apoptotic cell surface, the most fundamental of which is phosphatidylserine (PtdSer). Externalization of this phospholipid is catalysed by scramblase enzymes, several of which are activated by caspase cleavage. PtdSer is detected both by macrophage receptors that bind to this phospholipid directly and by receptors that bind to a soluble bridging protein that is independently bound to PtdSer. Prominent among the latter receptors are the MER and AXL receptor tyrosine kinases. Eat-me signals also trigger macrophages to engulf virus-infected or metabolically traumatized, but still living, cells, and this 'murder by phagocytosis' may be a common phenomenon. Finally, the localized presentation of PtdSer and other eat-me signals on delimited cell surface domains may enable the phagocytic pruning of these 'locally dead' domains by macrophages, most notably by microglia of the central nervous system.
Topics: Animals; Antigens, Surface; Apoptosis; Humans; Macrophages; Membrane Proteins; Milk Proteins; Phagocytosis; Phosphatidylserines; Receptor Protein-Tyrosine Kinases; c-Mer Tyrosine Kinase
PubMed: 31019284
DOI: 10.1038/s41577-019-0167-y -
Progress in Lipid Research Oct 2014Phosphatidylserine (PS) is the major anionic phospholipid class particularly enriched in the inner leaflet of the plasma membrane in neural tissues. PS is synthesized... (Review)
Review
Phosphatidylserine (PS) is the major anionic phospholipid class particularly enriched in the inner leaflet of the plasma membrane in neural tissues. PS is synthesized from phosphatidylcholine or phosphatidylethanolamine by exchanging the base head group with serine, and this reaction is catalyzed by phosphatidylserine synthase 1 and phosphatidylserine synthase 2 located in the endoplasmic reticulum. Activation of Akt, Raf-1 and protein kinase C signaling, which supports neuronal survival and differentiation, requires interaction of these proteins with PS localized in the cytoplasmic leaflet of the plasma membrane. Furthermore, neurotransmitter release by exocytosis and a number of synaptic receptors and proteins are modulated by PS present in the neuronal membranes. Brain is highly enriched with docosahexaenoic acid (DHA), and brain PS has a high DHA content. By promoting PS synthesis, DHA can uniquely expand the PS pool in neuronal membranes and thereby influence PS-dependent signaling and protein function. Ethanol decreases DHA-promoted PS synthesis and accumulation in neurons, which may contribute to the deleterious effects of ethanol intake. Improvement of some memory functions has been observed in cognitively impaired subjects as a result of PS supplementation, but the mechanism is unclear.
Topics: Animals; Biosynthetic Pathways; Brain; Cell Differentiation; Cell Survival; Docosahexaenoic Acids; Humans; Models, Biological; Neurons; Phosphatidylserines
PubMed: 24992464
DOI: 10.1016/j.plipres.2014.06.002 -
The EMBO Journal Aug 2020Neuronal circuit assembly requires the fine balance between synapse formation and elimination. Microglia, through the elimination of supernumerary synapses, have an...
Neuronal circuit assembly requires the fine balance between synapse formation and elimination. Microglia, through the elimination of supernumerary synapses, have an established role in this process. While the microglial receptor TREM2 and the soluble complement proteins C1q and C3 are recognized as key players, the neuronal molecular components that specify synapses to be eliminated are still undefined. Here, we show that exposed phosphatidylserine (PS) represents a neuronal "eat-me" signal involved in microglial-mediated pruning. In hippocampal neuron and microglia co-cultures, synapse elimination can be partially prevented by blocking accessibility of exposed PS using Annexin V or through microglial loss of TREM2. In vivo, PS exposure at both hippocampal and retinogeniculate synapses and engulfment of PS-labeled material by microglia occurs during established developmental periods of microglial-mediated synapse elimination. Mice deficient in C1q, which fail to properly refine retinogeniculate connections, have elevated presynaptic PS exposure and reduced PS engulfment by microglia. These data provide mechanistic insight into microglial-mediated synapse pruning and identify a novel role of developmentally regulated neuronal PS exposure that is common among developing brain structures.
Topics: Animals; Coculture Techniques; Complement C1q; Complement C3; Hippocampus; Membrane Glycoproteins; Mice; Mice, Knockout; Microglia; Neurons; Phosphatidylserines; Receptors, Immunologic; Synapses
PubMed: 32657463
DOI: 10.15252/embj.2020105380 -
Nature Reviews. Molecular Cell Biology Aug 2023Cellular membranes function as permeability barriers that separate cells from the external environment or partition cells into distinct compartments. These membranes are... (Review)
Review
Cellular membranes function as permeability barriers that separate cells from the external environment or partition cells into distinct compartments. These membranes are lipid bilayers composed of glycerophospholipids, sphingolipids and cholesterol, in which proteins are embedded. Glycerophospholipids and sphingolipids freely move laterally, whereas transverse movement between lipid bilayers is limited. Phospholipids are asymmetrically distributed between membrane leaflets but change their location in biological processes, serving as signalling molecules or enzyme activators. Designated proteins - flippases and scramblases - mediate this lipid movement between the bilayers. Flippases mediate the confined localization of specific phospholipids (phosphatidylserine (PtdSer) and phosphatidylethanolamine) to the cytoplasmic leaflet. Scramblases randomly scramble phospholipids between leaflets and facilitate the exposure of PtdSer on the cell surface, which serves as an important signalling molecule and as an 'eat me' signal for phagocytes. Defects in flippases and scramblases cause various human diseases. We herein review the recent research on the structure of flippases and scramblases and their physiological roles. Although still poorly understood, we address the mechanisms by which they translocate phospholipids between lipid bilayers and how defects cause human diseases.
Topics: Humans; Lipid Bilayers; Phospholipids; Cell Membrane; Glycerophospholipids; Phosphatidylserines
PubMed: 37106071
DOI: 10.1038/s41580-023-00604-z -
Circulation Research Jan 2024Single-nucleotide polymorphisms linked with the rs1474868 T allele ( [mitofusin-2] T/T) in the human mitochondrial fusion protein gene are associated with reduced...
BACKGROUND
Single-nucleotide polymorphisms linked with the rs1474868 T allele ( [mitofusin-2] T/T) in the human mitochondrial fusion protein gene are associated with reduced platelet RNA expression and platelet counts. This study investigates the impact of MFN2 on megakaryocyte and platelet biology.
METHODS
Mice with megakaryocyte/platelet deletion of ( [ conditional knockout]) were generated using Pf4-Cre crossed with floxed mice. Human megakaryocytes were generated from cord blood and platelets isolated from healthy subjects genotyped for rs1474868. Ex vivo approaches assessed mitochondrial morphology, function, and platelet activation responses. In vivo measurements included endogenous/transfused platelet life span, tail bleed time, transient middle cerebral artery occlusion, and pulmonary vascular permeability/hemorrhage following lipopolysaccharide-induced acute lung injury.
RESULTS
Mitochondria was more fragmented in megakaryocytes derived from mice and from human cord blood with T/T genotype compared with control megakaryocytes. Human resting platelets of T/T genotype had reduced MFN2 protein, diminished mitochondrial membrane potential, and an increased rate of phosphatidylserine exposure during ex vivo culture. Platelet counts and platelet life span were reduced in mice accompanied by an increased rate of phosphatidylserine exposure in resting platelets, especially aged platelets, during ex vivo culture. also decreased platelet mitochondrial membrane potential (basal) and activated mitochondrial oxygen consumption rate, reactive oxygen species generation, calcium flux, platelet-neutrophil aggregate formation, and phosphatidylserine exposure following dual agonist activation. Ultimately, mice showed prolonged tail bleed times, decreased ischemic stroke infarct size after cerebral ischemia-reperfusion, and exacerbated pulmonary inflammatory hemorrhage following lipopolysaccharide-induced acute lung injury. Analysis of SNPs in the iSPAAR study (Identification of SNPs Predisposing to Altered ALI Risk) identified a significant association between and 28-day mortality in patients with acute respiratory distress syndrome.
CONCLUSIONS
Mfn2 preserves mitochondrial phenotypes in megakaryocytes and platelets and influences platelet life span, function, and outcomes of stroke and lung injury.
Topics: Aged; Animals; Humans; Mice; Acute Lung Injury; Blood Platelets; Hemorrhage; Lipopolysaccharides; Mitochondria; Phosphatidylserines
PubMed: 38156445
DOI: 10.1161/CIRCRESAHA.123.322914 -
Science (New York, N.Y.) Jun 2014Phospholipids are asymmetrically distributed in the plasma membrane. This asymmetrical distribution is disrupted during apoptosis, exposing phosphatidylserine (PtdSer)...
Phospholipids are asymmetrically distributed in the plasma membrane. This asymmetrical distribution is disrupted during apoptosis, exposing phosphatidylserine (PtdSer) on the cell surface. Using a haploid genetic screen in human cells, we found that ATP11C (adenosine triphosphatase type 11C) and CDC50A (cell division cycle protein 50A) are required for aminophospholipid translocation from the outer to the inner plasma membrane leaflet; that is, they display flippase activity. ATP11C contained caspase recognition sites, and mutations at these sites generated caspase-resistant ATP11C without affecting its flippase activity. Cells expressing caspase-resistant ATP11C did not expose PtdSer during apoptosis and were not engulfed by macrophages, which suggests that inactivation of the flippase activity is required for apoptotic PtdSer exposure. CDC50A-deficient cells displayed PtdSer on their surface and were engulfed by macrophages, indicating that PtdSer is sufficient as an "eat me" signal.
Topics: Adenosine Triphosphatases; Apoptosis; Caspases; Cell Line; Cell Membrane; Genetic Testing; Humans; Membrane Proteins; Membrane Transport Proteins; Phosphatidylserines; Phospholipid Transfer Proteins; Protein Transport
PubMed: 24904167
DOI: 10.1126/science.1252809 -
The Journal of Cell Biology Jun 2021TMEM41B and VMP1 are integral membrane proteins of the endoplasmic reticulum (ER) and regulate the formation of autophagosomes, lipid droplets (LDs), and lipoproteins....
TMEM41B and VMP1 are integral membrane proteins of the endoplasmic reticulum (ER) and regulate the formation of autophagosomes, lipid droplets (LDs), and lipoproteins. Recently, TMEM41B was identified as a crucial host factor for infection by all coronaviruses and flaviviruses. The molecular function of TMEM41B and VMP1, which belong to a large evolutionarily conserved family, remains elusive. Here, we show that TMEM41B and VMP1 are phospholipid scramblases whose deficiency impairs the normal cellular distribution of cholesterol and phosphatidylserine. Their mechanism of action on LD formation is likely to be different from that of seipin. Their role in maintaining cellular phosphatidylserine and cholesterol homeostasis may partially explain their requirement for viral infection. Our results suggest that the proper sorting and distribution of cellular lipids are essential for organelle biogenesis and viral infection.
Topics: Autophagosomes; Autophagy; Cholesterol; Endoplasmic Reticulum; HeLa Cells; Humans; Lipid Droplets; Membrane Proteins; Phosphatidylserines; Protein Transport
PubMed: 33929485
DOI: 10.1083/jcb.202103105 -
Critical Reviews in Biochemistry and... Apr 2020P4-ATPases, a subfamily of P-type ATPases, translocate cell membrane phospholipids from the exoplasmic/luminal leaflet to the cytoplasmic leaflet to generate and... (Review)
Review
P4-ATPases, a subfamily of P-type ATPases, translocate cell membrane phospholipids from the exoplasmic/luminal leaflet to the cytoplasmic leaflet to generate and maintain membrane lipid asymmetry. Exposure of phosphatidylserine (PS) in the exoplasmic leaflet is well known to transduce critical signals for apoptotic cell clearance and platelet coagulation. PS exposure is also involved in many other biological processes, including myoblast and osteoclast fusion, and the immune response. Moreover, mounting evidence suggest that PS exposure is critical for neuronal regeneration and degeneration. In apoptotic cells, PS exposure is induced by irreversible activation of scramblases and inactivation of P4-ATPases. However, how PS is reversibly exposed and restored in viable cells during other biological processes remains poorly understood. In the present review, we discuss the physiological significance of reversible PS exposure in living cells, and the putative roles of flippases, floppases, and scramblases.
Topics: Animals; Apoptosis; Cell Membrane; Cell Survival; Cytoplasm; Humans; Lipid Bilayers; P-type ATPases; Phosphatidylserines; Phospholipid Transfer Proteins; Platelet Activation; Substrate Specificity
PubMed: 32408772
DOI: 10.1080/10409238.2020.1758624 -
Proceedings of the National Academy of... Nov 2018
Topics: Macrophages; Phosphatidylserines; Phospholipids; Precursor Cells, B-Lymphoid
PubMed: 30446613
DOI: 10.1073/pnas.1817485115 -
Biochemical Pharmacology Dec 2022In mammalian cells, phospholipids and cholesterol are assembled into bilayer membranes forming the plasma membrane, nuclear envelope, mitochondria, endoplasmic... (Review)
Review
In mammalian cells, phospholipids and cholesterol are assembled into bilayer membranes forming the plasma membrane, nuclear envelope, mitochondria, endoplasmic reticulum, Golgi apparatus, lysosomes, and endosomes. Phospholipids are divided into classes based on the molecular structures, including phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidic acid, phosphatidylinositol, phosphatidylglycerol, cardiolipin, and sphingomyelin. In addition to their structural roles, phospholipids play important roles in many cellular processes, such as membrane protein regulation, membrane trafficking, cell growth, apoptosis, and intracellular signaling. Thus, abnormal phospholipid metabolism is associated with various diseases. In mammalian cells, phospholipid classes are generated through several enzymatic steps, predominantly in the endoplasmic reticulum, mitochondria, and Golgi apparatus. In recent years, various enzymes involved in the biosynthesis of phospholipid classes have been identified. However, little is known about the regulatory mechanisms underlying the biosynthesis of phospholipid classes. Using our recently developed enzymatic fluorometric assays for all major phospholipid classes, we have demonstrated changes in phospholipid composition in intracellular organelles during cell growth. In this review, we summarize the current understanding of the properties and functions of phospholipid biosynthesis enzymes, and discuss their regulatory mechanisms.
Topics: Animals; Phospholipids; Endoplasmic Reticulum; Mitochondria; Cell Membrane; Phosphatidylserines; Mammals
PubMed: 36241095
DOI: 10.1016/j.bcp.2022.115296