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Genes & Genomics Sep 2020One of the key features of the plasma membrane is the asymmetrical distribution of phospholipids across it. Especially, phosphatidylserine (PS) exclusively locates on... (Review)
Review
One of the key features of the plasma membrane is the asymmetrical distribution of phospholipids across it. Especially, phosphatidylserine (PS) exclusively locates on its inner leaflet. Thus, the exposure of PS on the surface of cells could function as a signal initiating various cellular processes such as phagocytosis of apoptotic cells called efferocytosis, blood clotting, muscle formation, and viral entry. Indeed, PS on apoptotic cells stimulates phagocytes to engulf them and functions as an essential ligand for efferocytosis. Due to the importance of PS in efferocytosis, the existence of the PS receptor had been conceived. However, the PS receptor had not been revealed for a long time. Thus, the first identification of the PS receptor was significant excitement. Tim-4, a member of the T cell immunoglobulin and mucin domain containing family of genes, was one of PS receptors which first identified and received the greatest attention due to its expression in macrophages and relevance to autoimmune and allergic diseases. This review will serve to provide a comprehensive overview of Tim proteins as PS receptors.
Topics: Apoptosis; Humans; Macrophages; Membrane Proteins; Phagocytosis; Phosphatidylserines; Receptors, Cell Surface; Signal Transduction
PubMed: 32648232
DOI: 10.1007/s13258-020-00969-x -
Cell Communication and Signaling : CCS Nov 2019The numerous and diverse biological roles of Phosphatidylserine (PtdSer) are featured in this special issue. This review will focus on PtdSer as a cofactor required for... (Review)
Review
The numerous and diverse biological roles of Phosphatidylserine (PtdSer) are featured in this special issue. This review will focus on PtdSer as a cofactor required for stimulating TYRO3, AXL and MERTK - comprising the TAM family of receptor tyrosine kinases by their ligands Protein S (PROS1) and growth-arrest-specific 6 (GAS6) in inflammation and cancer. As PtdSer binding to TAMs is a requirement for their activation, the biological repertoire of PtdSer is now recognized to be broadened to include functions performed by TAMs. These include key homeostatic roles necessary for preserving a healthy steady state in different tissues, controlling inflammation and further additional roles in diseased states and cancer. The impact of PtdSer on inflammation and cancer through TAM signaling is a highly dynamic field of research. This review will focus on PtdSer as a necessary component of the TAM receptor-ligand complex, and for maximal TAM signaling. In particular, interactions between tumor cells and their immediate environment - the tumor microenvironment (TME) are highlighted, as both cancer cells and TME express TAMs and secrete their ligands, providing a nexus for a multifold of cross-signaling pathways which affects both immune cells and inflammation as well as tumor cell biology and growth. Here, we will highlight the current and emerging knowledge on the implications of PtdSer on TAM signaling, inflammation and cancer.
Topics: Animals; Humans; Inflammation; Neoplasms; Phosphatidylserines; Receptor Protein-Tyrosine Kinases; Signal Transduction; Tumor Microenvironment
PubMed: 31775787
DOI: 10.1186/s12964-019-0461-0 -
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 -
Apoptosis : An International Journal on... Apr 2024Eryptosis is a regulated cell death (RCD) of mature erythrocytes initially described as a counterpart of apoptosis for enucleated cells. However, over the recent years,... (Review)
Review
Eryptosis is a regulated cell death (RCD) of mature erythrocytes initially described as a counterpart of apoptosis for enucleated cells. However, over the recent years, a growing number of studies have emphasized certain differences between both cell death modalities. In this review paper, we underline the hallmarks of eryptosis and apoptosis and highlight resemblances and dissimilarities between both RCDs. We summarize and critically discuss differences in the impact of caspase-3, Ca signaling, ROS signaling pathways, opposing roles of casein kinase 1α, protein kinase C, Janus kinase 3, cyclin-dependent kinase 4, and AMP-activated protein kinase to highlight a certain degree of divergence between apoptosis and eryptosis. This review emphasizes the crucial importance of further studies that focus on deepening our knowledge of cell death machinery and identifying novel differences between cell death of nucleated and enucleated cells. This might provide evidence that erythrocytes can be defined as viable entities capable of programmed cell destruction. Additionally, the revealed cell type-specific patterns in cell death can facilitate the development of cell death-modulating therapeutic agents.
Topics: Apoptosis; Eryptosis; Erythrocytes; Signal Transduction; Cell Death; Calcium; Phosphatidylserines; Reactive Oxygen Species
PubMed: 38036865
DOI: 10.1007/s10495-023-01915-4 -
Cell Reports Oct 2022Oral and esophageal squamous cell carcinomas (SCCs) are associated with high mortality, yet the molecular mechanisms underlying these malignancies are largely unclear....
Oral and esophageal squamous cell carcinomas (SCCs) are associated with high mortality, yet the molecular mechanisms underlying these malignancies are largely unclear. We show that DNA hypermethylation of otubain 2 (OTUB2), a previously recognized oncogene, drives tongue and esophageal SCC initiation and drug resistance. Mechanistically, OTUB2 promotes the deubiquitination and phosphorylation of signal transducer and activator of transcription 1 (STAT1) and subsequently regulates the transcription of calmodulin-like protein 3 (CALML3). Activation of CALML3-mediated mitochondrial calcium signaling promotes oxidative phosphorylation (OXPHOS) and the synthesis of phosphatidylserine (PS). In mouse models, orally administered soybean-derived PS inhibits SCC initiation in cells with low OTUB2 expression and increases their sensitivity to chemotherapy. Our study indicates that the OTUB2/STAT1/CALML3/PS axis plays tumor-suppressive roles and shows the potential of PS administration as a strategy for the treatment and prevention of tongue and esophageal SCCs.
Topics: Animals; Mice; Calmodulin; Cell Line, Tumor; DNA; Phosphatidylserines; Signal Transduction; STAT1 Transcription Factor; Thiolester Hydrolases
PubMed: 36288705
DOI: 10.1016/j.celrep.2022.111561 -
Journal of Leukocyte Biology Sep 2019Arboviruses have been a huge threat for human health since the discovery of yellow fever virus in 1901. Arboviruses are arthropod born viruses, mainly transmitted by... (Review)
Review
Arboviruses have been a huge threat for human health since the discovery of yellow fever virus in 1901. Arboviruses are arthropod born viruses, mainly transmitted by mosquitoes and ticks, responsible for more than thousands of deaths annually. The Flavivirideae family is probably the most clinically relevant, as it is composed of very important agents, such as dengue, yellow fever, West Nile, Japanese encephalitis, and, recently, Zika virus. Intriguingly, despite their structural and genomic similarities, flaviviruses may cause conditions ranging from mild infections with fever, cutaneous rash, and headache, to very severe cases, such as hemorrhagic fever, encephalitis, Guillain-Barré syndrome, and microcephaly. These differences may greatly rely on viral burden, tissue tropism, and mechanisms of immune evasion that may depend on both viral and host genetic factors. Unfortunately, very little is known about the biology of these factors, and how they orchestrate these differences. In this context, viral structural proteins and host cellular receptors may have a great relevance, as their interaction dictates not only viral tissue tropism, but also a plethora on intracellular mechanisms that may greatly account for either failure or success of infection. A great number of viral receptors have been described so far, although there is still a huge gap in understanding their overall role during infection. Here we discuss some important aspects triggered after the interaction of flaviviruses and host membrane receptors, and how they change the overall outcome of the infection.
Topics: Animals; Flavivirus; Humans; Integrins; Phosphatidylserines; Receptors, Virus
PubMed: 31063609
DOI: 10.1002/JLB.MR1118-460R -
Movement Disorders : Official Journal... Aug 2023Chorea-acanthocytosis (ChAc) is associated with mutations of VPS13A, which encodes for chorein, a protein implicated in lipid transport at intracellular membrane contact...
BACKGROUND
Chorea-acanthocytosis (ChAc) is associated with mutations of VPS13A, which encodes for chorein, a protein implicated in lipid transport at intracellular membrane contact sites.
OBJECTIVES
The goal of this study was to establish the lipidomic profile of patients with ChAc.
METHODS
We analyzed 593 lipid species in the caudate nucleus (CN), putamen, and dorsolateral prefrontal cortex (DLPFC) from postmortem tissues of four patients with ChAc and six patients without ChAc.
RESULTS
We found increased levels of bis(monoacylglycerol)phosphate, sulfatide, lysophosphatidylserine, and phosphatidylcholine ether in the CN and putamen, but not in the DLPFC, of patients with ChAc. Phosphatidylserine and monoacylglycerol were increased in the CN and N-acyl phosphatidylserine in the putamen. N-acyl serine was decreased in the CN and DLPFC, whereas lysophosphatidylinositol was decreased in the DLPFC.
CONCLUSIONS
We present the first evidence of altered sphingolipid and phospholipid levels in the brains of patients with ChAc. Our observations are congruent with recent findings in cellular and animal models, and implicate defects of lipid processing in VPS13A disease pathophysiology. © 2023 International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.
Topics: Animals; Humans; Neuroacanthocytosis; Phospholipids; Phosphatidylserines; Vesicular Transport Proteins; Brain
PubMed: 37307400
DOI: 10.1002/mds.29445 -
Journal of the American Chemical Society Apr 2022TRAAK and TREK2 are two-pore domain K (K2P) channels and are modulated by diverse factors including temperature, membrane stretching, and lipids, such as phosphatidic...
TRAAK and TREK2 are two-pore domain K (K2P) channels and are modulated by diverse factors including temperature, membrane stretching, and lipids, such as phosphatidic acid. In addition, copper and zinc, both of which are essential for life, are known to regulate TREK2 and a number of other ion channels. However, the role of ions in the association of lipids with integral membrane proteins is poorly understood. Here, we discover cupric ions selectively modulate the binding of phosphatidylserine (PS) to TRAAK but not TREK2. Other divalent cations (Ca, Mg, and Zn) bind both channels but have no impact on binding PS and other lipids. Additionally, TRAAK binds more avidly to Cu and Zn than TREK2. In the presence of Cu, TRAAK binds similarly to PS with different acyl chains, indicating a crucial role of the serine headgroup in coordinating Cu. High-resolution native mass spectrometry (MS) enables the determination of equilibrium binding constants for distinct Cu-bound stoichiometries and uncovered the highest coupling factor corresponds to a 1:1 PS-to-Cu ratio. Interestingly, the next three highest coupling factors had a ∼1.5:1 PS-to-Cu ratio. Our findings bring forth the role of cupric ions as an essential cofactor in selective TRAAK-PS interactions.
Topics: Cations, Divalent; Phosphatidylserines; Potassium Channels, Tandem Pore Domain
PubMed: 35421309
DOI: 10.1021/jacs.2c00612 -
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