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Cell Reports Sep 2022Mitochondria are dynamic organelles essential for cell survival whose structural and functional integrity rely on selective and regulated transport of lipids from/to the...
Mitochondria are dynamic organelles essential for cell survival whose structural and functional integrity rely on selective and regulated transport of lipids from/to the endoplasmic reticulum (ER) and across the mitochondrial intermembrane space. As they are not connected by vesicular transport, the exchange of lipids between ER and mitochondria occurs at membrane contact sites. However, the mechanisms and proteins involved in these processes are only beginning to emerge. Here, we show that the main physiological localization of the lipid transfer proteins ORP5 and ORP8 is at mitochondria-associated ER membrane (MAM) subdomains, physically linked to the mitochondrial intermembrane space bridging (MIB)/mitochondrial contact sites and cristae junction organizing system (MICOS) complexes that bridge the two mitochondrial membranes. We also show that ORP5/ORP8 mediate non-vesicular transport of phosphatidylserine (PS) lipids from the ER to mitochondria by cooperating with the MIB/MICOS complexes. Overall our study reveals a physical and functional link between ER-mitochondria contacts involved in lipid transfer and intra-mitochondrial membrane contacts maintained by the MIB/MICOS complexes.
Topics: Endoplasmic Reticulum; Mitochondria; Mitochondrial Membranes; Mitochondrial Proteins; Phosphatidylserines
PubMed: 36130504
DOI: 10.1016/j.celrep.2022.111364 -
Seminars in Immunopathology Aug 2021For a long time, host cell death during parasitic infection has been considered a reflection of tissue damage, and often associated with disease pathogenesis. However,... (Review)
Review
For a long time, host cell death during parasitic infection has been considered a reflection of tissue damage, and often associated with disease pathogenesis. However, during their evolution, protozoan and helminth parasites have developed strategies to interfere with cell death so as to spread and survive in the infected host, thereby ascribing a more intriguing role to infection-associated cell death. In this review, we examine the mechanisms used by intracellular and extracellular parasites to respectively inhibit or trigger programmed cell death. We further dissect the role of the prototypical "eat-me signal" phosphatidylserine (PtdSer) which, by being exposed on the cell surface of damaged host cells as well as on some viable parasites via a process of apoptotic mimicry, leads to their recognition and up-take by the neighboring phagocytes. Although barely dissected so far, the engagement of different PtdSer receptors on macrophages, by shaping the host immune response, affects the overall infection outcome in models of both protozoan and helminth infections. In this scenario, further understanding of the molecular and cellular regulation of the PtdSer exposing cell-macrophage interaction might allow the identification of new therapeutic targets for the management of parasitic infection.
Topics: Animals; Apoptosis; Humans; Macrophages; Parasites; Parasitic Diseases; Phosphatidylserines
PubMed: 34279684
DOI: 10.1007/s00281-021-00875-8 -
Advanced Drug Delivery Reviews Apr 2016Clearance of apoptotic debris is a vital role of the innate immune system. Drawing upon principles of apoptotic clearance, convenient delivery vehicles including... (Review)
Review
Clearance of apoptotic debris is a vital role of the innate immune system. Drawing upon principles of apoptotic clearance, convenient delivery vehicles including intrinsic anti-inflammatory characteristics and specificity to immune cells can be engineered to aid in drug delivery. In this article, we examine the use of phosphatidylserine (PtdSer), the well-known "eat-me" signal, in nanoparticle-based therapeutics making them highly desirable "meals" for phagocytic immune cells. Use of PtdSer facilitates engulfment of nanoparticles allowing for imaging and therapy in various pathologies and may result in immunomodulation. Furthermore, we discuss the targeting of the macrophages and other cells at sites of inflammation in disease. A thorough understanding of the immunobiology of "eat-me" signals is requisite for the successful application of "eat-me"-bearing materials in biomedical applications.
Topics: Animals; Diagnostic Imaging; Drug Carriers; Drug Therapy; Humans; Immunity, Innate; Pharmaceutical Preparations; Phosphatidylserines
PubMed: 26826436
DOI: 10.1016/j.addr.2016.01.009 -
Current Opinion in Hematology Sep 2015Platelet microparticles are small extracellular vesicles abundant in blood. The present review will introduce the mechanisms underlying the generation of microparticles,... (Review)
Review
PURPOSE OF REVIEW
Platelet microparticles are small extracellular vesicles abundant in blood. The present review will introduce the mechanisms underlying the generation of microparticles, and will describe the diverse microparticle subtypes identified to date. The most appropriate methodologies used to distinguish microparticle subtypes will be also presented.
RECENT FINDINGS
Both the megakaryocytes and platelets can generate microparticles. Circulating microparticles originating from megakaryocytes are distinguished from those derived from activated platelets by the presence of CD62P, LAMP-1, and immunoreceptor-based activation motif receptors. Close examination of platelet activation has shed light on a novel mechanism leading to microparticle production. Under physiologic flow, microparticles bud off from long membrane strands formed by activated platelets. Furthermore, mounting evidence supports the notion of microparticle heterogeneity. Platelet microparticles are commonly characterized by the expression of surface platelet antigens and phosphatidylserine. In fact, only a fraction of platelet microparticles harbor phosphatidylserine, and a distinct subset contains respiratory-competent mitochondria. During disease, the microparticle surface may undergo posttranslational modifications such as citrullination, further supporting the concept of microparticle diversity.
SUMMARY
An appreciation of the microparticle heterogeneity will support their development as potential biomarkers and may reveal functions unique to each microparticle subtype in health and disease.
Topics: Blood Platelets; Cell-Derived Microparticles; Flow Cytometry; Humans; Megakaryocytes; Mitochondria; Phosphatidylserines; Platelet Activation
PubMed: 26214207
DOI: 10.1097/MOH.0000000000000166 -
Trends in Cell Biology Mar 2017Positive-strand RNA viruses are the largest group of RNA viruses on Earth and cellular membranes are critical for all aspects of their life cycle, from entry and... (Review)
Review
Positive-strand RNA viruses are the largest group of RNA viruses on Earth and cellular membranes are critical for all aspects of their life cycle, from entry and replication to exit. In particular, membranes serve as platforms for replication and as carriers to transmit these viruses to other cells, the latter either as an envelope surrounding a single virus or as the vesicle containing a population of viruses. Notably, many animal and human viruses appear to induce and exploit phosphatidylinositol 4-phosphate/cholesterol-enriched membranes for replication, whereas many plant and insect-vectored animal viruses utilize phosphatidylethanolamine/cholesterol-enriched membranes for the same purpose; and phosphatidylserine-enriched membrane carriers are widely used by both single and populations of viruses for transmission. Here I discuss the implications for viral pathogenesis and therapeutic development of this remarkable convergence on specific membrane lipid blueprints for replication and transmission.
Topics: Animals; Extracellular Vesicles; Humans; Lipids; Phosphatidylinositol Phosphates; Phosphatidylserines; Virus Diseases; Virus Replication
PubMed: 27838086
DOI: 10.1016/j.tcb.2016.09.011 -
Immunological Reviews Nov 2017Necroptosis is one the best-characterized forms of regulated necrosis. Necroptosis is mediated by the kinase activities of receptor interacting protein kinase-1 and... (Review)
Review
Necroptosis is one the best-characterized forms of regulated necrosis. Necroptosis is mediated by the kinase activities of receptor interacting protein kinase-1 and receptor interacting protein kinase-3, which eventually lead to the activation of mixed lineage kinase domain-like. Necroptosis is characterized by rapid permeabilization of the plasma membrane, which is associated with the release of the cell content and subsequent exposure of damage-associated molecular patterns (DAMPs) and cytokines/chemokines. This release underlies the immunogenic nature of necroptotic cancer cells and their ability to induce efficient anti-tumor immunity. Triggering necroptosis has become especially important in experimental cancer treatments as an alternative to triggering apoptosis because one of the hallmarks of cancer is the blockade or evasion of apoptosis. In this review, we discuss recent advances in necroptosis research and the functional consequences of necroptotic cancer cell death, with focus on its immunogenicity and its role in the activation of anti-tumor immunity. Next, we discuss the molecular mechanisms of phosphatidylserine exposure during necroptosis and its role in the recognition of necroptotic cells. We also highlight the complex role of the necroptotic pathway in tumor promotion and suppression and in metastasis. Future studies will show whether necroptosis is truly a better strategy to overcome apoptosis resistance and provide the insights needed for development of novel treatment strategies for cancer.
Topics: Animals; Apoptosis; Cancer Vaccines; Cell Death; Cytokines; DNA; DNA Damage; Humans; Immunotherapy; Necrosis; Phosphatidylserines; Tumor Escape
PubMed: 29027225
DOI: 10.1111/imr.12583 -
Biochimica Et Biophysica Acta Apr 2015Ras proteins assemble into transient nanoclusters on the plasma membrane. Nanoclusters are the sites of Ras effector recruitment and activation and are therefore... (Review)
Review
Ras proteins assemble into transient nanoclusters on the plasma membrane. Nanoclusters are the sites of Ras effector recruitment and activation and are therefore essential for signal transmission. The dynamics of nanocluster formation and disassembly result in interesting emergent properties including high-fidelity signal transmission. More recently the lipid structure of Ras nanoclusters has been reported and shown to contribute to isoform-specific Ras signaling. In addition specific lipids play critical roles in mediating the formation, stability and dynamics of Ras nanoclusters. In consequence the spatiotemporal organization of these lipids has emerged as important and novel regulators of Ras function. This article is part of a Special Issue entitled: Nanoscale membrane organisation and signalling.
Topics: Animals; Cell Membrane; Humans; Lipids; Nanoparticles; Phosphatidylserines; Signal Transduction; ras Proteins
PubMed: 25234412
DOI: 10.1016/j.bbamcr.2014.09.008 -
Seminars in Cancer Biology Oct 2018Cancer is a leading cause of mortality and morbidity globally. Many prominent cancer-associated molecules have been identified over the recent years which include EGFR,... (Review)
Review
Cancer is a leading cause of mortality and morbidity globally. Many prominent cancer-associated molecules have been identified over the recent years which include EGFR, CD44, TGFbRII, HER2, miR-497, NMP22, BTA, Fibrin/FDP etc. These biomarkers are often used for screening, detection, diagnosis, prognosis, prediction and monitoring of cancer development. Phosphatidylserine (PS) is an essential component in all human cells which is present on the inner leaflet of the cell membrane. The oxidative stress causes exposure of PS on the surface of the vascular endothelium in the cancer cells (lung, breast, pancreatic, bladder, skin, brain metastasis, rectal adenocarcinoma etc.) but not on the normal cells. The external PS is regulated by calcium-dependent flippase activity. Cancer cell lines with high surface PS have low flippase activity and high intracellular calcium content. Human Annexin-V, PS targeting antibodies (PGN635 and bavituximab and mch1N11), lysosomal protein, phospholipid Saposin C dioleoylphosphatidylserine (SapC-DOPS), peptide-peptoid hybrid PPS1, PS-binding 14-mer peptide (PSBP-6) and hexapeptide (E3) have been reported to target PS present on cancer cell surface. High expression of CD47 inhibits tumor cell phagocytosis by macrophages. The PS cancer biomarker has also been used to target the drugs to cancer cells specifically without affecting other healthy cells. Currently, the fusion protein (FP) consisting of L-methionase linked to human Annexin-V has been reported to target the cancer cells. The FP catalyzes the conversion of non-toxic prodrug selenomethionine into toxic methyl selenol which thus also prevents the methionine (essential amino acid) supplementation to the cancer cells.
Topics: Biomarkers, Tumor; Cell Membrane; Humans; Models, Biological; Molecular Targeted Therapy; Neoplasms; Phosphatidylserines; Protein Binding; Saposins
PubMed: 28870843
DOI: 10.1016/j.semcancer.2017.08.012 -
Clinical Immunology (Orlando, Fla.) Nov 2023Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by the presence of antiphospholipid antibodies (aPLs), which can lead to thrombosis and pregnancy...
Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by the presence of antiphospholipid antibodies (aPLs), which can lead to thrombosis and pregnancy complications. Within the diverse range of aPLs, anti-phosphatidylserine/prothrombin antibodies (aPS/PT) have gained significance in clinical practice. The detection of aPS/PT has proven valuable in identifying APS patients and stratifying their risk, especially when combined with other aPL tests like lupus anticoagulant (LA) and anti-β-glycoprotein I (aβGPI). Multivariate analyses have confirmed aPS/PT as an independent risk factor for vascular thrombosis and obstetric complications, with its inclusion in the aPL score and the Global Anti-Phospholipid Syndrome Score (GAPSS) aiding in risk evaluation. However, challenges remain in the laboratory testing of aPS/PT, including the need for assay standardization and its lower sensitivity in certain patient populations. Further research is necessary to validate the clinical utility of aPS/PT antibodies in APS diagnosis, risk stratification, and management.
Topics: Female; Pregnancy; Humans; Antiphospholipid Syndrome; Prothrombin; Phosphatidylserines; Antibodies, Antiphospholipid; beta 2-Glycoprotein I; Thrombosis
PubMed: 37838215
DOI: 10.1016/j.clim.2023.109804 -
The Journal of Biological Chemistry 2021Formations of myofibers, osteoclasts, syncytiotrophoblasts, and fertilized zygotes share a common step, cell-cell fusion. Recent years have brought about considerable... (Review)
Review
Formations of myofibers, osteoclasts, syncytiotrophoblasts, and fertilized zygotes share a common step, cell-cell fusion. Recent years have brought about considerable progress in identifying some of the proteins involved in these and other cell-fusion processes. However, even for the best-characterized cell fusions, we still do not know the mechanisms that regulate the timing of cell-fusion events. Are they fully controlled by the expression of fusogenic proteins or do they also depend on some triggering signal that activates these proteins? The latter scenario would be analogous to the mechanisms that control the timing of exocytosis initiated by Ca influx and virus-cell fusion initiated by low pH- or receptor interaction. Diverse cell fusions are accompanied by the nonapoptotic exposure of phosphatidylserine at the surface of fusing cells. Here we review data on the dependence of membrane remodeling in cell fusion on phosphatidylserine and phosphatidylserine-recognizing proteins and discuss the hypothesis that cell surface phosphatidylserine serves as a conserved "fuse me" signal regulating the time and place of cell-fusion processes.
Topics: Cell Fusion; Exocytosis; Humans; Phosphatidylserines; Signal Transduction; Virus Internalization
PubMed: 33581114
DOI: 10.1016/j.jbc.2021.100411