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Bioarchitecture 2014Loss of plasma membrane asymmetry is a hallmark of apoptosis, but lipid bilayer asymmetry and loss of asymmetry can contribute to numerous cellular functions and... (Review)
Review
Loss of plasma membrane asymmetry is a hallmark of apoptosis, but lipid bilayer asymmetry and loss of asymmetry can contribute to numerous cellular functions and responses that are independent of programmed cell death. Exofacial exposure of phosphatidylserine occurs in lymphocytes and mast cells after antigenic stimulation and in the absence of apoptosis, suggesting that there is a functional requirement for phosphatidylserine exposure in immunocytes. In this review we examine current ideas as to the nature of this functional role in mast cell activation. Mechanistically, there is controversy as to the candidate proteins responsible for phosphatidylserine translocation from the internal to external leaflet, and here we review the candidacies of mast cell PLSCR1 and TMEM16F. Finally we examine the potential relationship between functionally important mast cell membrane perturbations and phosphatidylserine exposure during activation.
Topics: Apoptosis; Cell Membrane; Humans; Lipids; Mast Cells; Phosphatidylserines
PubMed: 25759911
DOI: 10.1080/19490992.2014.995516 -
Sensors (Basel, Switzerland) 2011Phosphatidylserine, a phospholipid with a negatively charged head-group, is an important constituent of eukaryotic cellular membranes. On the plasma membrane, rather... (Review)
Review
Phosphatidylserine, a phospholipid with a negatively charged head-group, is an important constituent of eukaryotic cellular membranes. On the plasma membrane, rather than being evenly distributed, phosphatidylserine is found preferentially in the inner leaflet. Disruption of this asymmetry, leading to the appearance of phosphatidylserine on the surface of the cell, is known to play a central role in both apoptosis and blood clotting. Despite its importance, comparatively little is known about phosphatidylserine in cells: its precise subcellular localization, transmembrane topology and intracellular dynamics are poorly characterized. The recent development of new, genetically-encoded probes able to detect phosphatidylserine within live cells, however, is leading to a more in-depth understanding of the biology of this phospholipid. This review aims to give an overview of the current methods for phosphatidylserine detection within cells, and some of the recent realizations derived from their use.
Topics: Animals; Antigens, Surface; Biosensing Techniques; Cell Membrane; Fluorescence; Humans; Phosphatidylserines
PubMed: 22319379
DOI: 10.3390/s110201744 -
Nature Communications Jun 2019Various studies have demonstrated that the two leaflets of cellular membranes interact, potentially through so-called interdigitation between the fatty acyl groups.... (Review)
Review
Various studies have demonstrated that the two leaflets of cellular membranes interact, potentially through so-called interdigitation between the fatty acyl groups. While the molecular mechanism underlying interleaflet coupling remains to be fully understood, recent results suggest interactions between the very-long-chain sphingolipids in the outer leaflet, and phosphatidylserine PS18:0/18:1 in the inner leaflet, and an important role for cholesterol for these interactions. Here we review the evidence that cross-linking of sphingolipids may result in clustering of phosphatidylserine and transfer of signals to the cytosol. Although much remains to be uncovered, the molecular properties and abundance of PS 18:0/18:1 suggest a unique role for this lipid.
Topics: Animals; Cell Line; Cell Membrane; Cholesterol; Cross-Linking Reagents; Cytosol; Humans; Lipid Bilayers; Phosphatidylserines; Sphingolipids
PubMed: 31227693
DOI: 10.1038/s41467-019-10711-1 -
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 -
Theranostics 2020Cancer is a leading cause of mortality and morbidity worldwide. Despite major improvements in current therapeutic methods, ideal therapeutic strategies for improved... (Review)
Review
Cancer is a leading cause of mortality and morbidity worldwide. Despite major improvements in current therapeutic methods, ideal therapeutic strategies for improved tumor elimination are still lacking. Recently, immunotherapy has attracted much attention, and many immune-active agents have been approved for clinical use alone or in combination with other cancer drugs. However, some patients have a poor response to these agents. New agents and strategies are needed to overcome such deficiencies. Phosphatidylserine (PS) is an essential component of bilayer cell membranes and is normally present in the inner leaflet. In the physiological state, PS exposure on the external leaflet not only acts as an engulfment signal for phagocytosis in apoptotic cells but also participates in blood coagulation, myoblast fusion and immune regulation in nonapoptotic cells. In the tumor microenvironment, PS exposure is significantly increased on the surface of tumor cells or tumor cell-derived microvesicles, which have innate immunosuppressive properties and facilitate tumor growth and metastasis. To date, agents targeting PS have been developed, some of which are under investigation in clinical trials as combination drugs for various cancers. However, controversial results are emerging in laboratory research as well as in clinical trials, and the efficiency of PS-targeting agents remains uncertain. In this review, we summarize recent progress in our understanding of the physiological and pathological roles of PS, with a focus on immune suppressive features. In addition, we discuss current drug developments that are based on PS-targeting strategies in both experimental and clinical studies. We hope to provide a future research direction for the development of new agents for cancer therapy.
Topics: Animals; Apoptosis; Cell Membrane; Humans; Immunotherapy; Neoplasms; Phosphatidylserines; Tumor Microenvironment
PubMed: 32802188
DOI: 10.7150/thno.45125 -
Cell Communication and Signaling : CCS Mar 2020Phosphatidylserine (PS) is an anionic phospholipid found on the membranes of a variety of organelles throughout the cell, most notably the plasma membrane. Under...
Phosphatidylserine (PS) is an anionic phospholipid found on the membranes of a variety of organelles throughout the cell, most notably the plasma membrane. Under homeostatic conditions, PS is typically restricted to the inner leaflet of the plasma membrane. However, during cellular activation and/or induction of cell death, PS is externalized on the outer surface via the activation of phospholipid scramblases. Externalized PS not only changes the biochemical and biophysical properties of the plasma membrane but also initiates a series of interactions between endogenous extracellular proteins as well as receptors on neighboring cells to stimulate engulfment (efferocytosis) that influence the surrounding immune milieu. In this thematic series published in Cell Communication and Signaling, we feature review articles that highlight recent work in the field of PS biology, including the biochemistry and physiological significance of PS externalization, therapeutic applications and efforts to target PS, as well as posit open questions that remain in the field.
Topics: Animals; Cell Communication; Cell Membrane; Communicable Diseases; Humans; Neoplasms; Phosphatidylserines; Signal Transduction
PubMed: 32160904
DOI: 10.1186/s12964-020-00543-8 -
Cell Death and Differentiation Jun 2016Apoptosis is an evolutionarily conserved and tightly regulated cell death modality. It serves important roles in physiology by sculpting complex tissues during... (Review)
Review
Apoptosis is an evolutionarily conserved and tightly regulated cell death modality. It serves important roles in physiology by sculpting complex tissues during embryogenesis and by removing effete cells that have reached advanced age or whose genomes have been irreparably damaged. Apoptosis culminates in the rapid and decisive removal of cell corpses by efferocytosis, a term used to distinguish the engulfment of apoptotic cells from other phagocytic processes. Over the past decades, the molecular and cell biological events associated with efferocytosis have been rigorously studied, and many eat-me signals and receptors have been identified. The externalization of phosphatidylserine (PS) is arguably the most emblematic eat-me signal that is in turn bound by a large number of serum proteins and opsonins that facilitate efferocytosis. Under physiological conditions, externalized PS functions as a dominant and evolutionarily conserved immunosuppressive signal that promotes tolerance and prevents local and systemic immune activation. Pathologically, the innate immunosuppressive effect of externalized PS has been hijacked by numerous viruses, microorganisms, and parasites to facilitate infection, and in many cases, establish infection latency. PS is also profoundly dysregulated in the tumor microenvironment and antagonizes the development of tumor immunity. In this review, we discuss the biology of PS with respect to its role as a global immunosuppressive signal and how PS is exploited to drive diverse pathological processes such as infection and cancer. Finally, we outline the rationale that agents targeting PS could have significant value in cancer and infectious disease therapeutics.
Topics: Animals; Antibodies; Apoptosis; Apoptosis Regulatory Proteins; Autoimmunity; Communicable Diseases; Humans; Membrane Glycoproteins; Neoplasms; Phosphatidylserines; Receptors, Cell Surface; Signal Transduction
PubMed: 26915293
DOI: 10.1038/cdd.2016.11 -
Transfusion Clinique Et Biologique :... Jun 2012Labile blood products contain phosphatidylserine-expressing cell dusts, including apoptotic cells and microparticles. These cell by-products are produced during blood... (Review)
Review
Labile blood products contain phosphatidylserine-expressing cell dusts, including apoptotic cells and microparticles. These cell by-products are produced during blood product process or storage and derived from the cells of interest that exert a therapeutic effect (red blood cells or platelets). Alternatively, phosphatidylserine-expressing cell dusts may also derived from contaminating cells, such as leukocytes, or may be already present in plasma, such as platelet-derived microparticles. These cell by-products present in labile blood products can be responsible for transfusion-induced immunomodulation leading to either transfusion-related acute lung injury (TRALI) or increased occurrence of post-transfusion infections or cancer relapse. In this review, we report data from the literature and our laboratory dealing with interactions between antigen-presenting cells and phosphatidylserine-expressing cell dusts, including apoptotic leukocytes and blood cell-derived microparticles. Then, we discuss how these phosphatidylserine-expressing cell by-products may influence transfusion.
Topics: Cell-Derived Microparticles; Humans; Inflammation; Phosphatidylserines; Transfusion Reaction
PubMed: 22677430
DOI: 10.1016/j.tracli.2012.02.002 -
Proceedings of the National Academy of... Apr 2023CD8 T cells are crucial for the clearance of viral infections. During the acute phase, proinflammatory conditions increase the amount of circulating phosphatidylserine...
CD8 T cells are crucial for the clearance of viral infections. During the acute phase, proinflammatory conditions increase the amount of circulating phosphatidylserine (PS) extracellular vesicles (EVs). These EVs interact especially with CD8 T cells; however, it remains unclear whether they can actively modulate CD8 T cell responses. In this study, we have developed a method to analyze cell-bound PS EVs and their target cells in vivo. We show that EV cell abundance increases during viral infection and that EVs preferentially bind to activated, but not naive, CD8 T cells. Superresolution imaging revealed that PS EVs attach to clusters of CD8 molecules on the T cell surface. Furthermore, EV-binding induces antigen (Ag)-specific TCR signaling and increased nuclear translocation of the transcription factor Nuclear factor of activated T-cells (NFATc1) in vivo. EV-decorated but not EV-free CD8 T cells are enriched for gene signatures associated with T-cell receptor signaling, early effector differentiation, and proliferation. Our data thus demonstrate that PS EVs provide Ag-specific adjuvant effects to activated CD8 T cells in vivo.
Topics: Humans; CD8-Positive T-Lymphocytes; Phosphatidylserines; Extracellular Vesicles; Virus Diseases; Cell Differentiation
PubMed: 37040405
DOI: 10.1073/pnas.2210047120 -
Molecular Cancer May 2016Unlike normal cells, cancer cells express high levels of phosphatidylserine on the extracellular leaflet of their cell membrane. Exploiting this characteristic, our lab... (Review)
Review
Unlike normal cells, cancer cells express high levels of phosphatidylserine on the extracellular leaflet of their cell membrane. Exploiting this characteristic, our lab developed a therapeutic agent that consists of the fusogenic protein, saposin C (SapC) which is embedded in dioleoylphosphatidylserine (DOPS) vesicles. These nanovesicles selectively target cancer cells and induce apoptosis. Here we review the data supporting use of SapC-DOPS to locate tumors for surgical resection or for treatment. In addition, there is important evidence suggesting that SapC-DOPS may also prove to be an effective novel cancer therapeutic reagent. Given that SapC-DOPS is easily labeled with lipophilic dyes, it has been combined with the far-red fluorescent dye, CellVue Maroon (CVM), for tumor targeting studies. We also have used contrast agents incorporated in the SapC-DOPS nanovesicles for computed tomography and magnetic resonance imaging, and review that data here. Administered intravenously, the fluorescently labeled SapC-DOPS traversed the blood-brain tumor barrier enabling identification of brain tumors. SapC-DOPS-CVM also detected a variety of other mouse tumors in vivo, rendering them observable by optical imaging using IVIS and multi-angle rotational optical imaging. Dye is detected within 30 min and remains within tumor for at least 7 days, whereas non-tumor tissues were unstained (some dye observed in the liver was transient, likely representing degradation products). Additionally, labeled SapC-DOPS ex vivo delineated tumors in human histological specimens. SapC-DOPS can also be labeled with contrast reagents for computed tomography or magnetic resonance imaging. In conclusion, labeled SapC-DOPS provides a convenient, specific, and nontoxic method for detecting tumors while concurrently offering a therapeutic benefit.
Topics: Animals; Cell Membrane; Contrast Media; Fluorescent Dyes; Humans; Models, Animal; Molecular Imaging; Multimodal Imaging; Nanoparticles; Neoplasms; Phosphatidylserines; Protein Binding; Saposins
PubMed: 27160923
DOI: 10.1186/s12943-016-0519-1