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Biochemical Society Transactions Oct 2022Phagocytosis triggered by the phospholipid phosphatidylserine (PS) is key for the removal of apoptotic cells in development, tissue homeostasis and infection. Modulation... (Review)
Review
Phagocytosis triggered by the phospholipid phosphatidylserine (PS) is key for the removal of apoptotic cells in development, tissue homeostasis and infection. Modulation of PS-mediated phagocytosis is an attractive target for therapeutic intervention in the context of atherosclerosis, neurodegenerative disease, and cancer. Whereas the mechanisms of target recognition, lipid and protein signalling, and cytoskeletal remodelling in opsonin-driven modes of phagocytosis are increasingly well understood, PS-mediated phagocytosis has remained more elusive. This is partially due to the involvement of a multitude of receptors with at least some redundancy in functioning, which complicates dissecting their contributions and results in complex downstream signalling networks. This review focusses on the receptors involved in PS-recognition, the signalling cascades that connect receptors to cytoskeletal remodelling required for phagocytosis, and recent progress in our understanding of how phagocytic cup formation is coordinated during PS-mediated phagocytosis.
Topics: Humans; Phosphatidylserines; Neurodegenerative Diseases; Apoptosis; Phagocytosis; Signal Transduction
PubMed: 36281986
DOI: 10.1042/BST20211254 -
Nature Reviews. Microbiology Aug 2015As opportunistic pathogens, viruses have evolved many elegant strategies to manipulate host cells for infectious entry and replication. Viral apoptotic mimicry, defined... (Review)
Review
As opportunistic pathogens, viruses have evolved many elegant strategies to manipulate host cells for infectious entry and replication. Viral apoptotic mimicry, defined by the exposure of phosphatidylserine - a marker for apoptosis - on the pathogen surface, is emerging as a common theme used by enveloped viruses to promote infection. Focusing on the four best described examples (vaccinia virus, dengue virus, Ebola virus and pseudotyped lentivirus), we summarize our current understanding of apoptotic mimicry as a mechanism for virus entry, binding and immune evasion. We also describe recent examples of non-enveloped viruses that use this mimicry strategy, and discuss future directions and how viral apoptotic mimicry could be targeted therapeutically.
Topics: Animals; Apoptosis; Humans; Immune Evasion; Molecular Mimicry; Phagocytes; Phosphatidylserines; Receptors, Cell Surface; Virus Internalization; Viruses
PubMed: 26052667
DOI: 10.1038/nrmicro3469 -
The Journal of Cell Biology Jun 2021TMEM41B and VMP1 are integral membrane proteins of the endoplasmic reticulum (ER) and regulate the formation of autophagosomes, lipid droplets (LDs), and lipoproteins....
TMEM41B and VMP1 are integral membrane proteins of the endoplasmic reticulum (ER) and regulate the formation of autophagosomes, lipid droplets (LDs), and lipoproteins. Recently, TMEM41B was identified as a crucial host factor for infection by all coronaviruses and flaviviruses. The molecular function of TMEM41B and VMP1, which belong to a large evolutionarily conserved family, remains elusive. Here, we show that TMEM41B and VMP1 are phospholipid scramblases whose deficiency impairs the normal cellular distribution of cholesterol and phosphatidylserine. Their mechanism of action on LD formation is likely to be different from that of seipin. Their role in maintaining cellular phosphatidylserine and cholesterol homeostasis may partially explain their requirement for viral infection. Our results suggest that the proper sorting and distribution of cellular lipids are essential for organelle biogenesis and viral infection.
Topics: Autophagosomes; Autophagy; Cholesterol; Endoplasmic Reticulum; HeLa Cells; Humans; Lipid Droplets; Membrane Proteins; Phosphatidylserines; Protein Transport
PubMed: 33929485
DOI: 10.1083/jcb.202103105 -
Developmental Cell Jul 2023Cell extrusion is a universal mode of cell removal from tissues, and it plays an important role in regulating cell numbers and eliminating unwanted cells. However, the...
Cell extrusion is a universal mode of cell removal from tissues, and it plays an important role in regulating cell numbers and eliminating unwanted cells. However, the underlying mechanisms of cell delamination from the cell layer are unclear. Here, we report a conserved execution mechanism of apoptotic cell extrusion. We found extracellular vesicle (EV) formation in extruding mammalian and Drosophila cells at a site opposite to the extrusion direction. Lipid-scramblase-mediated local exposure of phosphatidylserine is responsible for EV formation and is crucial for executing cell extrusion. Inhibition of this process disrupts prompt cell delamination and tissue homeostasis. Although the EV has hallmarks of an apoptotic body, its formation is governed by the mechanism of microvesicle formation. Experimental and mathematical modeling analysis illustrated that EV formation promotes neighboring cells' invasion. This study showed that membrane dynamics play a crucial role in cell exit by connecting the actions of the extruding cell and neighboring cells.
Topics: Animals; Phosphatidylserines; Apoptosis; Drosophila; Endocytosis; Extracellular Vesicles; Mammals
PubMed: 37315563
DOI: 10.1016/j.devcel.2023.05.008 -
Current Opinion in Immunology Feb 2020In various biological processes, phosphatidylserine (PtdSer) that is normally sequestered to the inner leaflet of the plasma membrane (PM) is exposed to the cell... (Review)
Review
In various biological processes, phosphatidylserine (PtdSer) that is normally sequestered to the inner leaflet of the plasma membrane (PM) is exposed to the cell surface. When platelets are activated, they expose PtdSer to activate the blood-clotting factors. Cells undergoing apoptosis and senescent neutrophils expose PtdSer that is recognized as an 'eat me' signal by phagocytes for clearance. The PtdSer-exposure and its internalization are mediated by phospholipid scramblases and flippases, respectively. Both have recently been molecularly identified, and their functional mechanism and physiological roles are being elucidated.
Topics: Adenosine Triphosphatases; Animals; Cell Membrane; Humans; Models, Molecular; Phosphatidylserines
PubMed: 31837595
DOI: 10.1016/j.coi.2019.11.009 -
Biochemistry. Biokhimiia Mar 2022Apoptosis is the most thoroughly studied type of regulated cell death. Certain events, such as externalization of phosphatidylserine (PS) into the outer leaflet of... (Review)
Review
Apoptosis is the most thoroughly studied type of regulated cell death. Certain events, such as externalization of phosphatidylserine (PS) into the outer leaflet of plasma membrane, mitochondrial outer membrane permeabilization, caspase cascade activation, DNA fragmentation and blebbing, are widely considered to be hallmarks of apoptosis as well as being traditionally viewed as irreversible. This review shows that under particular circumstances these events can also participate in physiological processes not associated with initiation of apoptosis, such as cell differentiation, division, and motility, as well as non-apoptotic types of cell death. Moreover, these events may often be reversible. This review focuses on three processes: phosphatidylserine externalization, blebbing, and activation of apoptotic caspases. Mitochondrial outer membrane permeabilization and DNA fragmentation are not discussed.
Topics: Apoptosis; Caspases; Phosphatidylserines
PubMed: 35526851
DOI: 10.1134/S0006297922030014 -
Neuroscience Research Jun 2021Phospholipids are asymmetrically distributed at the plasma membrane. Phosphatidylserine (PtdSer) is exclusively located in the inner leaflet of the cell membrane while... (Review)
Review
Phospholipids are asymmetrically distributed at the plasma membrane. Phosphatidylserine (PtdSer) is exclusively located in the inner leaflet of the cell membrane while phosphatidylcholine (PtdCho) and glycolipids are mainly located in the outer leaflet of the membrane. However, this asymmetry is disrupted in various physiological situations, and PtdSer is exposed on the cell surface. In platelets, exposed PtdSer functions as a scaffold for the coagulation reaction, while in dead cells, exposed PtdSer serves as an "Eat-me" signal for efferocytosis. In the developing brain, synaptic connections are over-formed during the fetal period, but about half of the neurons are removed by apoptosis, and synaptic and dendritic compartments of living neurons are also removed by phagocytes. During these processes, glial cells such as microglia and astrocyte engulf unwanted dead cells and compartments in living cells using several phagocytic receptors, recognizing PtdSer by direct binding or an indirect way using secreted molecules. Based on recent findings, we will discuss how the compartments in living neurons are eliminated for the neuronal circuit plasticity.
Topics: Apoptosis; Brain; Cell Membrane; Phosphatidylserines; Phospholipids
PubMed: 33476682
DOI: 10.1016/j.neures.2021.01.003 -
The EMBO Journal Jul 2023The mature mammalian brain connectome emerges during development via the extension and pruning of neuronal connections. Glial cells have been identified as key players...
The mature mammalian brain connectome emerges during development via the extension and pruning of neuronal connections. Glial cells have been identified as key players in the phagocytic elimination of neuronal synapses and projections. Recently, phosphatidylserine has been identified as neuronal "eat-me" signal that guides elimination of unnecessary input sources, but the associated transduction systems involved in such pruning are yet to be described. Here, we identified Xk-related protein 8 (Xkr8), a phospholipid scramblase, as a key factor for the pruning of axons in the developing mammalian brain. We found that mouse Xkr8 is highly expressed immediately after birth and required for phosphatidylserine exposure in the hippocampus. Mice lacking Xkr8 showed excess excitatory nerve terminals, increased density of cortico-cortical and cortico-spinal projections, aberrant electrophysiological profiles of hippocampal neurons, and global brain hyperconnectivity. These data identify phospholipid scrambling by Xkr8 as a central process in the labeling and discrimination of developing neuronal projections for pruning in the mammalian brain.
Topics: Animals; Mice; Phospholipid Transfer Proteins; Apoptosis Regulatory Proteins; Apoptosis; Phosphatidylserines; Axons; Neuronal Plasticity; Mammals; Membrane Proteins
PubMed: 37211968
DOI: 10.15252/embj.2022111790 -
Journal of Cancer Research and Clinical... Dec 2021Cancer immunotherapy is a major breakthrough in tumor therapy and has been used in monotherapy or combination therapy. However, it has been associated with poor immune... (Review)
Review
Cancer immunotherapy is a major breakthrough in tumor therapy and has been used in monotherapy or combination therapy. However, it has been associated with poor immune tolerance in some patients or immune-related adverse events. Therefore, ideal and reliable tumor elimination strategies are urgently needed to overcome these shortcomings. Phosphatidylserine (PS) is a negatively charged phospholipid, usually present in the inner lobules of eukaryotic cell membranes. Under certain physiological or pathological conditions, PS may be exposed on the outer leaflets of apoptotic cells serving as recognition signals by phagocytes and modulating the immune response. On the contrary, increased exposure of PS in the tumor microenvironment can significantly antagonize the body's anti-tumor immunity, thereby promoting tumor growth and metastasis. During radiotherapy and chemotherapy, PS-mediated immunosuppression increases the PS levels in necrotic tissue in the tumor microenvironment, further suppressing tumor immunity. PS-targeted therapy is a promising strategy in cancer immunotherapy. It inhibits tumor growth and improves the anti-tumor activity of immune checkpoint inhibitors. A comprehensive understanding of the mechanism of PS-targeted therapy opens up a new perspective for future cancer immunotherapies.
Topics: Animals; Humans; Immune Checkpoint Inhibitors; Immunotherapy; Neoplasms; Phosphatidylserines; Tumor Microenvironment
PubMed: 34499223
DOI: 10.1007/s00432-021-03792-3 -
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