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Role of flippases, scramblases and transfer proteins in phosphatidylserine subcellular distribution.Traffic (Copenhagen, Denmark) Jan 2015It is well known that lipids are heterogeneously distributed throughout the cell. Most lipid species are synthesized in the endoplasmic reticulum (ER) and then... (Review)
Review
It is well known that lipids are heterogeneously distributed throughout the cell. Most lipid species are synthesized in the endoplasmic reticulum (ER) and then distributed to different cellular locations in order to create the distinct membrane compositions observed in eukaryotes. However, the mechanisms by which specific lipid species are trafficked to and maintained in specific areas of the cell are poorly understood and constitute an active area of research. Of particular interest is the distribution of phosphatidylserine (PS), an anionic lipid that is enriched in the cytosolic leaflet of the plasma membrane. PS transport occurs by both vesicular and non-vesicular routes, with members of the oxysterol-binding protein family (Osh6 and Osh7) recently implicated in the latter route. In addition, the flippase activity of P4-ATPases helps build PS membrane asymmetry by preferentially translocating PS to the cytosolic leaflet. This asymmetric PS distribution can be used as a signaling device by the regulated activation of scramblases, which rapidly expose PS on the extracellular leaflet and play important roles in blood clotting and apoptosis. This review will discuss recent advances made in the study of phospholipid flippases, scramblases and PS-specific lipid transfer proteins, as well as how these proteins contribute to subcellular PS distribution.
Topics: Adenosine Triphosphatases; Animals; Biological Transport; Cell Membrane; Endoplasmic Reticulum; Humans; Phosphatidylserines; Phospholipids
PubMed: 25284293
DOI: 10.1111/tra.12233 -
International Journal of Molecular... Mar 2024As an important functional protein molecule in the human body, human annexin A5 (hAnxA5) is widely found in human cells and body fluids. hAnxA5, the smallest type of... (Review)
Review
As an important functional protein molecule in the human body, human annexin A5 (hAnxA5) is widely found in human cells and body fluids. hAnxA5, the smallest type of annexin, performs a variety of biological functions by reversibly and specifically binding phosphatidylserine (PS) in a calcium-dependent manner and plays an important role in many human physiological and pathological processes. The free state hAnxA5 exists in the form of monomers and usually forms a polymer in a specific self-assembly manner when exerting biological activity. This review systematically discusses the current knowledge and understanding of hAnxA5 from three perspectives: physiopathological relevance, diagnostic value, and therapeutic utility. AnxA5 affects the occurrence and development of many physiopathological processes. Moreover, hAnxA5 can be used independently or in combination as a biomarker of physiopathological phenomena for the diagnosis of certain diseases. Importantly, based on the properties of hAnxA5, many novel drug candidates have been designed and prepared for application in actual medical practice. However, there are also some gaps and shortcomings in AnxA5 research. This in-depth study will not only expand the understanding of structural and functional relationships but also promote the application of hAnxA5 in the field of biomedicine.
Topics: Humans; Annexin A5; Apoptosis; Calcium; Calcium, Dietary; Phosphatidylserines
PubMed: 38474114
DOI: 10.3390/ijms25052865 -
Brazilian Journal of Medical and... Jun 2005Apoptosis is the most common phenotype observed when cells die through programmed cell death. The morphologic and biochemical changes that characterize apoptotic cells... (Review)
Review
Apoptosis is the most common phenotype observed when cells die through programmed cell death. The morphologic and biochemical changes that characterize apoptotic cells depend on the activation of a diverse set of genes. Apoptosis is essential for multicellular organisms since their development and homeostasis are dependent on extensive cell renewal. In fact, there is strong evidence for the correlation between the emergence of multicellular organisms and apoptosis during evolution. On the other hand, no obvious advantages can be envisaged for unicellular organisms to carry the complex machinery required for programmed cell death. However, accumulating evidence shows that free-living and parasitic protozoa as well as yeasts display apoptotic markers. This phenomenon has been related to altruistic behavior, when a subpopulation of protozoa or yeasts dies by apoptosis, with clear benefits for the entire population. Recently, phosphatidylserine (PS) exposure and its recognition by a specific receptor (PSR) were implicated in the infectivity of amastigote forms of Leishmania, an obligatory vertebrate intramacrophagic parasite, showing for the first time that unicellular organisms use apoptotic features for the establishment and/or maintenance of infection. Here we focus on PS exposure in the outer leaflet of the plasma membrane--an early hallmark of apoptosis--and how it modulates the inflammatory activity of phagocytic cells. We also discuss the possible mechanisms by which PS exposure can define Leishmania survival inside host cells and the evolutionary implications of apoptosis at the unicellular level.
Topics: Animals; Apoptosis; Arginase; Host-Parasite Interactions; Immune System; Leishmania; Macrophages; Phosphatidylserines
PubMed: 15933773
DOI: 10.1590/s0100-879x2005000600001 -
Physiological Reviews Apr 2016Phosphatidylserine (PS) is a major component of membrane bilayers whose change in distribution between inner and outer leaflets is an important physiological signal.... (Review)
Review
Phosphatidylserine (PS) is a major component of membrane bilayers whose change in distribution between inner and outer leaflets is an important physiological signal. Normally, members of the type IV P-type ATPases spend metabolic energy to create an asymmetric distribution of phospholipids between the two leaflets, with PS confined to the cytoplasmic membrane leaflet. On occasion, membrane enzymes, known as scramblases, are activated to facilitate transbilayer migration of lipids, including PS. Recently, two proteins required for such randomization have been identified: TMEM16F, a scramblase regulated by elevated intracellular Ca(2+), and XKR8, a caspase-sensitive protein required for PS exposure in apoptotic cells. Once exposed at the cell surface, PS regulates biochemical reactions involved in blood coagulation, and bone mineralization, and also regulates a variety of cell-cell interactions. Exposed on the surface of apoptotic cells, PS controls their recognition and engulfment by other cells. This process is exploited by parasites to invade their host, and in specialized form is used to maintain photoreceptors in the eye and modify synaptic connections in the brain. This review discusses what is known about the mechanism of PS exposure at the surface of the plasma membrane of cells, how actors in the extracellular milieu sense surface exposed PS, and how this recognition is translated to downstream consequences of PS exposure.
Topics: Animals; Anoctamins; Apoptosis Regulatory Proteins; Cell Communication; Cell Membrane; Cytophagocytosis; Humans; Membrane Proteins; Phosphatidylserines; Phospholipid Transfer Proteins
PubMed: 26936867
DOI: 10.1152/physrev.00020.2015 -
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 -
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 -
Aging Cell Aug 2004It is important for the resolution of inflammation that the number and activity of immune cells are reduced. Clearance of immune cells may be achieved by apoptosis and... (Review)
Review
It is important for the resolution of inflammation that the number and activity of immune cells are reduced. Clearance of immune cells may be achieved by apoptosis and phagocytosis of cell fragments by macrophages. However, signalling shutdown by immune cells committed to apoptosis occurs early in the progression of these cells towards fragmentation and, it could be argued, is a key feature of apoptosis. There is surprisingly little known about the mechanisms that underlie this signalling shutdown, in particular the shutdown of Ca(2+) influx. The consequences and the potential mechanisms by which Ca(2+) influx shutdown is achieved are discussed. In addition, the potential consequences for cell signalling of cytochrome c release from mitochondria and of phosphatidyl-serine externalization are discussed. The aim of the review is therefore to highlight the evidence for various signalling shutdown strategies in immune cells that may limit their activity during progression towards apoptosis.
Topics: Apoptosis; Calcium Signaling; Cell Death; Cell Membrane; Cytochromes c; Humans; Immune System; Lymphocytes; Mitochondria; Neutrophils; Phosphatidylserines; Signal Transduction
PubMed: 15268747
DOI: 10.1111/j.1474-9728.2004.00100.x -
Nature Communications Feb 2018Molecular logic gates are expected to play an important role on the way to information processing therapeutic agents, especially considering the wide variety of physical...
Molecular logic gates are expected to play an important role on the way to information processing therapeutic agents, especially considering the wide variety of physical and chemical responses that they can elicit in response to the inputs applied. Here, we show that a 1:2 demultiplexer based on a Zn-terpyridine-Bodipy conjugate with a quenched fluorescent emission, is efficient in photosensitized singlet oxygen generation as inferred from trap compound experiments and cell culture data. However, once the singlet oxygen generated by photosensitization triggers apoptotic response, the Zn complex then interacts with the exposed phosphatidylserine lipids in the external leaflet of the membrane bilayer, autonomously switching off singlet oxygen generation, and simultaneously switching on a bright emission response. This is the confirmatory signal of the cancer cell death by the action of molecular automaton and the confinement of unintended damage by excessive singlet oxygen production.
Topics: Apoptosis; Cell Line; Cell Membrane; Cells; Flow Cytometry; Humans; Phosphatidylserines; Photochemistry; Photosensitizing Agents; Singlet Oxygen; Zinc
PubMed: 29476048
DOI: 10.1038/s41467-018-03259-z -
Sports Medicine (Auckland, N.Z.) 2006Phosphatidylserine (PtdSer) is a ubiquitous phospholipid species that is normally located within the inner leaflet of the cell membrane. PtdSer has been implicated in a... (Review)
Review
Phosphatidylserine (PtdSer) is a ubiquitous phospholipid species that is normally located within the inner leaflet of the cell membrane. PtdSer has been implicated in a myriad of membrane-related functions. As a cofactor for a variety of enzymes, PtdSer is thought to be important in cell excitability and communication. PtdSer has also been shown to regulate a variety of neuroendocrine responses that include the release of acetylcholine, dopamine and noradrenaline. Additionally, PtdSer has been extensively demonstrated to influence tissue responses to inflammation. Finally, PtdSer has the potential to act as an effective antioxidant, especially in response to iron-mediated oxidation. The majority of the available research that has investigated the effects of PtdSer supplementation on humans has concentrated on memory and cognitive function; patients experiencing some degree of cognitive decline have traditionally been the main focus of investigation. Although investigators have administered PtdSer through intravenous and oral routes, oral supplementation has wider appeal. Indeed, PtdSer is commercially available as an oral supplement intended to improve cognitive function, with recommended doses usually ranging from 100 to 500 mg/day. The main sources that have been used to derive PtdSer for supplements are bovine-cortex (BC-PtdSer) and soy (S-PtdSer); however, due to the possibility of transferring infection through the consumption of prion contaminated brain, S-PtdSer is the preferred supplement for use in humans. Although the pharmacokinetics of PtdSer have not been fully elucidated, it is likely that oral supplementation leads to small but quantifiable increases in the PtdSer content within the cell membrane.A small number of peer-reviewed full articles exist that investigate the effects of PtdSer supplementation in the exercising human. Early research indicated that oral supplementation with BC-PtdSer 800 mg/day moderated exercise-induced changes to the hypothalamo-pituitary-adrenal axis in untrained participants. Subsequently, this finding was extended to suggest that S-PtdSer 800 mg/day reduced the cortisol response to overtraining during weight training while improving feeling of well-being and decreasing perceived muscle soreness. However, equivocal findings from our laboratory might suggest that the dose required to undertake this neuroendocrine action may vary between participants.Interestingly, recent findings demonstrating that short-term supplementation with S-PtdSer 750 mg/day improved exercise capacity during high-intensity cycling and tended to increase performance during intermittent running might suggest an innovative application for this supplement. With the findings from the existing body of literature in mind, this article focuses on the potential effects of PtdSer supplementation in humans during and following exercise.
Topics: Clinical Trials as Topic; Dietary Supplements; Exercise Tolerance; Humans; Neurosecretory Systems; Oxygen Consumption; Phosphatidylserines; Physical Exertion
PubMed: 16869708
DOI: 10.2165/00007256-200636080-00003 -
Apoptosis : An International Journal on... Sep 2010Cells are able to execute apoptosis by activating series of specific biochemical reactions. One of the most prominent characteristics of cell death is the... (Review)
Review
Cells are able to execute apoptosis by activating series of specific biochemical reactions. One of the most prominent characteristics of cell death is the externalization of phosphatidylserine (PS), which in healthy cells resides predominantly in the inner leaflet of the plasma membrane. These features have made PS-externalization a well-explored phenomenon to image cell death for diagnostic purposes. In addition, it was demonstrated that under certain conditions viable cells express PS at their surface such as endothelial cells of tumor blood vessels, stressed tumor cells and hypoxic cardiomyocytes. Hence, PS has become a potential target for therapeutic strategies aiming at Targeted Drug Delivery. In this review we highlight the biomarker PS and various PS-binding compounds that have been employed to target PS for diagnostic purposes. We emphasize the 35 kD human protein annexin A5, that has been developed as a Molecular Imaging agent to measure cell death in vitro, and non-invasively in vivo in animal models and in patients with cardiovascular diseases and cancer. Recently focus has shifted from diagnostic towards therapeutic applications employing annexin A5 in strategies to deliver drugs to cells that express PS at their surface.
Topics: Animals; Annexin A5; Diagnosis; Diagnostic Imaging; Drug Therapy; Humans; Phosphatidylserines; Protein Binding; Synaptotagmin I
PubMed: 20440562
DOI: 10.1007/s10495-010-0503-y