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Cell Communication and Signaling : CCS May 2023Extracellular vesicles (EVs) are important mediators of intercellular communication in the tumour microenvironment. Many studies suggest that cancer cells release higher...
Extracellular vesicles (EVs) are important mediators of intercellular communication in the tumour microenvironment. Many studies suggest that cancer cells release higher amounts of EVs exposing phosphatidylserine (PS) at the surface. There are lots of interconnections between EVs biogenesis and autophagy machinery. Modulation of autophagy can probably affect not only the quantity of EVs but also their content, which can deeply influence the resulting pro-tumourigenic or anticancer effect of autophagy modulators. In this study, we found that autophagy modulators autophinib, CPD18, EACC, bafilomycin A1 (BAFA1), 3-hydroxychloroquine (HCQ), rapamycin, NVP-BEZ235, Torin1, and starvation significantly alter the composition of the protein content of phosphatidylserine-positive EVs (PS-EVs) produced by cancer cells. The greatest impact had HCQ, BAFA1, CPD18, and starvation. The most abundant proteins in PS-EVs were proteins typical for extracellular exosomes, cytosol, cytoplasm, and cell surface involved in cell adhesion and angiogenesis. PS-EVs protein content involved mitochondrial proteins and signalling molecules such as SQSTM1 and TGFβ1 pro-protein. Interestingly, PS-EVs contained no commonly determined cytokines, such as IL-6, IL-8, GRO-α, MCP-1, RANTES, and GM-CSF, which indicates that secretion of these cytokines is not predominantly mediated through PS-EVs. Nevertheless, the altered protein content of PS-EVs can still participate in the modulation of the fibroblast metabolism and phenotype as p21 was accumulated in fibroblasts influenced by EVs derived from CPD18-treated FaDu cells. The altered protein content of PS-EVs (data are available via ProteomeXchange with identifier PXD037164) also provides information about the cellular compartments and processes that are affected by the applied autophagy modulators. Video Abstract.
Topics: Phosphatidylserines; Extracellular Vesicles; Autophagy; Cytokines; Exosomes
PubMed: 37226246
DOI: 10.1186/s12964-023-01126-z -
Life Science Alliance Aug 2022The evolutionarily conserved extended synaptotagmin (E-Syt) proteins are calcium-activated lipid transfer proteins that function at contacts between the ER and plasma...
The evolutionarily conserved extended synaptotagmin (E-Syt) proteins are calcium-activated lipid transfer proteins that function at contacts between the ER and plasma membrane (ER-PM contacts). However, roles of the E-Syt family members in PM lipid organisation remain incomplete. Among the E-Syt family, the yeast tricalbin (Tcb) proteins are essential for PM integrity upon heat stress, but it is not known how they contribute to PM maintenance. Using quantitative lipidomics and microscopy, we find that the Tcb proteins regulate phosphatidylserine homeostasis at the PM. Moreover, upon heat-induced membrane stress, Tcb3 co-localises with the PM protein Sfk1 that is implicated in PM phospholipid asymmetry and integrity. The Tcb proteins also control the PM targeting of the known phosphatidylserine effector Pkc1 upon heat-induced stress. Phosphatidylserine has evolutionarily conserved roles in PM organisation, integrity, and repair. We propose that phospholipid regulation is an ancient essential function of E-Syt family members required for PM integrity.
Topics: Cell Membrane; Homeostasis; Membrane Proteins; Phosphatidylserines; Phospholipids; Synaptotagmins
PubMed: 35440494
DOI: 10.26508/lsa.202201430 -
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 -
Immunological Reviews Nov 2017Programmed cell death (apoptosis) is an integral part of tissue homeostasis in complex organisms, allowing for tissue turnover, repair, and renewal while simultaneously... (Review)
Review
Programmed cell death (apoptosis) is an integral part of tissue homeostasis in complex organisms, allowing for tissue turnover, repair, and renewal while simultaneously inhibiting the release of self antigens and danger signals from apoptotic cell-derived constituents that can result in immune activation, inflammation, and autoimmunity. Unlike cells in culture, the physiological fate of cells that die by apoptosis in vivo is their rapid recognition and engulfment by phagocytic cells (a process called efferocytosis). To this end, apoptotic cells express specific eat-me signals, such as externalized phosphatidylserine (PS), that are recognized in a specific context by receptors to initiate signaling pathways for engulfment. The importance of carefully regulated recognition and clearance pathways is evident in the spectrum of inflammatory and autoimmune disorders caused by defects in PS receptors and signaling molecules. However, in recent years, several additional cell death pathways have emerged, including immunogenic cell death, necroptosis, pyroptosis, and netosis that interweave different cell death pathways with distinct innate and adaptive responses from classical apoptosis that can shape long-term host immunity. In this review, we discuss the role of different cell death pathways in terms of their immune potential outcomes specifically resulting in specific cell corpse/phagocyte interactions (phagocytic synapses) that impinge on host immunity, with a main emphasis on tolerance and cancer immunotherapy.
Topics: Animals; Apoptosis; Humans; Immune Tolerance; Immunity; Phagocytes; Phagocytosis; Phosphatidylserines; Signal Transduction; Tumor Microenvironment
PubMed: 29027226
DOI: 10.1111/imr.12587 -
Cell Communication and Signaling : CCS Oct 2019Phosphatidylserine (PtdSer), an essential constituent of eukaryotic membranes, is the most abundant anionic phospholipid in the eukaryotic cell accounting for up to 10%... (Review)
Review
Phosphatidylserine (PtdSer), an essential constituent of eukaryotic membranes, is the most abundant anionic phospholipid in the eukaryotic cell accounting for up to 10% of the total cellular lipid. Much of what is known about PtdSer is the role exofacial PtdSer plays in apoptosis and blood clotting. However, PtdSer is generally not externally exposed in healthy cells and plays a vital role in several intracellular signaling pathways, though relatively little is known about the precise subcellular localization, transmembrane topology and intracellular dynamics of PtdSer within the cell. The recent development of new, genetically-encoded probes able to detect phosphatidylserine is leading to a more in-depth understanding of the biology of this phospholipid. This review aims to give an overview of recent developments in our understanding of the role of PtdSer in intracellular signaling events derived from the use of these recently developed methods of phosphatidylserine detection.
Topics: Animals; Cells; Humans; Intracellular Space; Phosphatidylserines
PubMed: 31615534
DOI: 10.1186/s12964-019-0438-z -
Traffic (Copenhagen, Denmark) Feb 2015Over the past two decades, most of the genes specifying lipid synthesis and metabolism in yeast have been identified and characterized. Several of these biosynthetic... (Review)
Review
Over the past two decades, most of the genes specifying lipid synthesis and metabolism in yeast have been identified and characterized. Several of these biosynthetic genes and their encoded enzymes have provided valuable tools for the genetic and biochemical dissection of interorganelle lipid transport processes in yeast. One such pathway involves the synthesis of phosphatidylserine (PtdSer) in the endoplasmic reticulum (ER), and its non-vesicular transport to the site of phosphatidylserine decarboxylase2 (Psd2p) in membranes of the Golgi and endosomal sorting system. In this review, we summarize the identification and characterization of the yeast phosphatidylserine decarboxylases, and examine their role in studies of the transport-dependent pathways of de novo synthesis of phosphatidylethanolamine (PtdEtn). The emerging picture of the Psd2p-specific transport pathway is one in which the enzyme and its non-catalytic N-terminal domains act as a hub to nucleate the assembly of a multiprotein complex, which facilitates PtdSer transport at membrane contact sites between the ER and Golgi/endosome membranes. After transport to the catalytic site of Psd2p, PtdSer is decarboxylated to form PtdEtn, which is disseminated throughout the cell to support the structural and functional needs of multiple membranes.
Topics: Biological Transport; Carboxy-Lyases; Endoplasmic Reticulum; Phosphatidylserines; Yeasts
PubMed: 25355612
DOI: 10.1111/tra.12236 -
Cell Cycle (Georgetown, Tex.) Nov 2016
Topics: ADAM17 Protein; Cell Membrane; Enzyme Activation; Phosphatidylserines
PubMed: 27463373
DOI: 10.1080/15384101.2016.1211449 -
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 -
Biochimica Et Biophysica Acta.... Apr 2023The ability of arginine-rich peptides to cross the lipid bilayer and enter cytoplasm, unlike their lysine-based analogues, is intensively studied in the context of...
Interaction of guanidinium and ammonium cations with phosphatidylcholine and phosphatidylserine lipid bilayers - Calorimetric, spectroscopic and molecular dynamics simulations study.
The ability of arginine-rich peptides to cross the lipid bilayer and enter cytoplasm, unlike their lysine-based analogues, is intensively studied in the context of cell-penetrating peptides. Although the experiments have not yet reconstructed their internalization mechanism, the computational studies have shown that the type or charge of lipid polar groups is one of the crucial factors in their translocation. In order to gain more detailed insight into the interaction of guanidinium (Gdm) and ammonium (NH) cations, as important building blocks in arginine and lysine amino acids, with lipid bilayers, we conducted the experimental and computational study that tackles this phenomenon. The adsorption of Gdm and NH on lipid bilayers prepared from a zwitterionic (DPPC) and an anionic (DPPS) lipid was examined by thermoanalytic and spectroscopic techniques. Using temperature-dependent UV-Vis spectroscopy and DSC calorimetry we determined the impact of Gdm and NH on the thermotropic properties of lipid bilayers. FTIR data, along with molecular dynamics simulations, unraveled the molecular-level details on the nature of their interactions, showing the proton transfer between NH and DPPS, but not between Gdm and DPPS. The findings originated from this work imply that Gdm and NH form qualitatively different interactions with lipids of different charge which is reflected in the physico-chemical interactions that arginine-and lysine-based peptides establish at a complex and chemically heterogeneous environment such as the biological membrane.
Topics: Lipid Bilayers; Phosphatidylserines; Guanidine; Molecular Dynamics Simulation; Lysine; Spectrum Analysis; Lecithins; Cell-Penetrating Peptides; Calorimetry; Arginine; Cations
PubMed: 36739930
DOI: 10.1016/j.bbamem.2023.184122 -
Actas Espanolas de Psiquiatria Sep 2017Alzheimer disease and the other neurodegenerative dementias as yet have no curative treatment. For this reason, the prevention of these conditions and...
Alzheimer disease and the other neurodegenerative dementias as yet have no curative treatment. For this reason, the prevention of these conditions and non-pharmacological treatments are important fields of research at present. The Mediterranean diet (rich in fruits, vegetables, legumes, and olive oil, with regular fish consumption and low consumption of dairy products and meats) has been shown to reduce the incidence of mild cognitive impairment (MCI) and, probably, the conversion of MCI to dementia. Vitamins, especially vitamin E and the vitamins of the B group, have also been associated with the prevention of cognitive impairment due to their antioxidant effects. Ginkgo biloba is one of the most widely used supplements in the world for cognitive improvement because of its possible effects as a vasodilator and facilitator of cerebral vascularization. Green tea polyphenols have shown beneficial effects in different diseases, including cognitive impairment. Cerebral aging is associated with changes in the lipid composition of neuronal membranes, so it has been suggested that treatment with phospholipids like phosphatidylcholine and phosphatidylserine could favor cognitive improvement. Similarly, polyunsaturated and omega-3 fatty acids, and docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) supplements are associated with a beneficial effect on cognitive function due to the cumulative summation of factors that ultimately favor membrane permeability and neuronal functioning.
Topics: Cognitive Dysfunction; Dietary Supplements; Fatty Acids, Omega-3; Humans; Phosphatidylcholines; Phosphatidylserines; Vitamins
PubMed: 29171642
DOI: No ID Found