scholarly journals TMEM16F phospholipid scramblase mediates trophoblast fusion and placental development

2019 ◽  
Author(s):  
Yang Zhang ◽  
Trieu Le ◽  
Ryan Grabau ◽  
Zahra Mohseni ◽  
Hoejeong Kim ◽  
...  
Keyword(s):  
Cell Surface ◽  
Cell Fusion ◽  
Placental Development ◽  
Cellular Mechanisms ◽  
Developmental Defects ◽  
Phospholipid Scramblase ◽  
A Cell ◽  
Fusion Signal ◽  
Multicellular Organisms ◽  
Cell Cell

AbstractCell-cell fusion or syncytialization is fundamental to the reproduction, development and homeostasis of multicellular organisms. In addition to various cell-type specific fusogenic proteins, cell surface externalization of phosphatidylserine (PS), a universal eat-me signal in apoptotic cells, has been observed in different cell-fusion events. Nevertheless, molecular underpinnings of PS externalization and cellular mechanisms of PS-facilitated cell-cell fusion are unclear. Here we report that TMEM16F, a Ca2+-activated phospholipid scramblase (CaPLSase), plays an indispensable role in placental trophoblast fusion by translocating PS to the cell surface independent of apoptosis. Consistent with its essential role in trophoblast fusion, the placentas from TMEM16F-deficient mice exhibit deficiency in syncytialization, placental developmental defects and perinatal lethality. Our findings thus identify a cell-cell fusion mechanism by which TMEM16F CaPLSase-dependent externalization of PS serves as a critical cell fusion signal to facilitate trophoblast syncytialization and placental development.

scholarly journals TMEM16F phospholipid scramblase mediates trophoblast fusion and placental development

2020 ◽  
Vol 6 (19) ◽  
pp. eaba0310 ◽  
Author(s):  
Yang Zhang ◽  
Trieu Le ◽  
Ryan Grabau ◽  
Zahra Mohseni ◽  
Hoejeong Kim ◽  
...  
Keyword(s):  
Cell Surface ◽  
Cell Fusion ◽  
Cell Types ◽  
Placental Development ◽  
Cellular Mechanisms ◽  
Phospholipid Scramblase ◽  
Perinatal Lethality ◽  
Cell Type Specific ◽  
Multicellular Organisms ◽  
Cell Cell

Cell-cell fusion or syncytialization is fundamental to the reproduction, development, and homeostasis of multicellular organisms. In addition to various cell type–specific fusogenic proteins, cell surface externalization of phosphatidylserine (PS), a universal eat-me signal in apoptotic cells, has been observed in different cell fusion events. Nevertheless, the molecular underpinnings of PS externalization and cellular mechanisms of PS-facilitated cell-cell fusion are unclear. Here, we report that TMEM16F, a Ca2+-activated phospholipid scramblase (CaPLSase), plays an essential role in placental trophoblast fusion by translocating PS to cell surface independent of apoptosis. The placentas from the TMEM16F knockout mice exhibit deficiency in trophoblast syncytialization and placental development, which lead to perinatal lethality. We thus identified a new biological function of TMEM16F CaPLSase in trophoblast fusion and placental development. Our findings provide insight into understanding cell-cell fusion mechanism of other cell types and on mitigating pregnancy complications such as miscarriage, intrauterine growth restriction, and preeclampsia.

Studies of membrane fusion. I. Paramyxovirus-induced cell fusion, a scanning electron-microscope study

1977 ◽  
Vol 28 (1) ◽  
pp. 179-188
Author(s):  
S. Knutton ◽  
D. Jackson ◽  
M. Ford
Keyword(s):  
Cell Surface ◽  
Cell Fusion ◽  
Hela Cells ◽  
Cell Swelling ◽  
Cell Contact ◽  
Cell Agglutination ◽  
Scanning Electron Microscope Study ◽  
Virus Particles ◽  
Scanning Electron ◽  
Cell Cell

Fusion of erythrocytes and HeLa cells with Sendai and Newcastle disease viruses has been studied by scanning electron microscopy. Most virus particles are spherical but vary in diameter from approximately 200 to approximately 600 nm. At 4 degrees C virus particles bind randomly to the cell surface and at high cell densities cross-linking of adjacent cells by virus particles results in cell agglutination. Cell-cell fusion takes place when the agglutinated cell suspension is warmed to 37 degrees C. Fusion is initiated at sites of cell-cell contact and is accompanied in all cases by cell swelling. In the case of suspension HeLa cells, virally mediated cell swelling involves an ‘unfolding’ of cell surface microvilli and results in the formation of smooth-surfaced single or fused cells. With erythrocytes, swelling results in haemolysis. There is a dramatic reduction in the numbers of virus particles bound to cells following fusion.

scholarly journals A generic cell surface ligand system for studying cell-cell recognition

2019 ◽  
Author(s):  
Eleanor M Denham ◽  
Michael I Barton ◽  
Susannah M Black ◽  
Marcus J Bridge ◽  
Ben de Wet ◽  
...  
Keyword(s):  
Cell Surface ◽  
Surface Density ◽  
Cell Receptor ◽  
Surface Receptors ◽  
Ligand System ◽  
Ligand Interactions ◽  
A Cell ◽  
Surface Ligand ◽  
Receptor Biology ◽  
Cell Cell

AbstractDose-response experiments are a mainstay of receptor biology studies and can reveal valuable insights into receptor function. Such studies of receptors that bind cell surface ligands are currently limited by the difficulty in manipulating the surface density of ligands at a cell-cell interface. Here we describe a generic cell surface ligand system that allows precise manipulation of cell surface ligand densities over several orders of magnitude. We validate the system for a range of immunoreceptors, including the T cell receptor (TCR), and show that this generic ligand stimulates via the TCR at a similar surface density as its native ligand. This system allows the effect of surface density, valency, dimensions, and affinity of the ligand to be manipulated. It can be readily extended to other receptor-cell surface ligand interactions, and will facilitate investigation into the activation of, and signal integration between, cell surface receptors.

The putative sponge aggregation receptor. Isolation and characterization of a molecule composed of scavenger receptor cysteine-rich domains and short consensus repeats

1998 ◽  
Vol 111 (17) ◽  
pp. 2635-2644 ◽  
Author(s):  
B. Blumbach ◽  
Z. Pancer ◽  
B. Diehl-Seifert ◽  
R. Steffen ◽  
J. Munkner ◽  
...  
Keyword(s):  
Cell Surface ◽  
Scavenger Receptor ◽  
Cell Surface Receptor ◽  
Functional Assay ◽  
Cdna Clones ◽  
The Third ◽  
Short Consensus Repeats ◽  
Isolation And Characterization ◽  
A Cell ◽  
Cell Cell

Porifera (sponges) are the oldest extant metazoan phylum. Dissociated sponge cells serve as a classic system to study processes of cell reaggregation. The reaggregation of dissociated cells is mediated by an extracellularly localized aggregation factor (AF), based on heterophilic interactions of the third order; the AF bridges two cells by ligating a cell-surface-bound aggregation receptor (AR). In the present study we report cloning, expression and immunohistochemical localization of a polypeptide from the marine sponge Geodia cydonium, which very likely represents the AR. The presumed AR gene gives rise to at least three forms of alternatively spliced transcripts of 6.5, 4.9 and 3.9 kb, as detected by northern blotting. Two cDNA clones corresponding to the shorter forms were already reported earlier; here we present an analysis of the largest. All three putative polypeptides feature scavenger receptor cysteine-rich (SRCR) domains. The largest form, SRCR-SCR-Car, is a cell-surface receptor of molecular mass 220 kDa, which is assumed to be the cell-adhesion receptor AR; the second form, SRCR-Re, is also a putative receptor of 166 kDa, while the third form, SRCR-Mo, is a soluble molecule of 129 kDa. The SRCR-SCR-Car molecule consists of fourteen SRCR domains, six short consensus repeats (SCRs), a C-terminal transmembrane domain and a cytoplasmic tail; its fourteenth SRCR domain features an Arg-Gly-Asp tripeptide. To obtain monoclonal antibodies, a 170-amino-acid-long polypeptide that is found in all three forms of the SRCR-containing proteins was expressed in E. coli. In a western blot of sponge cells lysate the monoclonal antibody raised against the recombinant polypeptide recognized two major immuno-reacting polypeptides (220 and 117 kDa) and two minor bands (36 and 32 kDa). The antibody was found to react with antigen(s) predominantly localized on the plasma membranes of cells, especially those of spherulous cells. In a functional assay Fab' fragments of the antibodies suppressed AF-mediated cell-cell reaggregation. Additionally, a recombinant SRCR-soluble fragment effectively inhibited AF-mediated cell-cell reaggregation. We conclude that the 220 kDa SRCR-containing protein of the sponge G. cydonium is very likely the AR.

scholarly journals Contribution of Endocytic Motifs in the Cytoplasmic Tail of Herpes Simplex Virus Type 1 Glycoprotein B to Virus Replication and Cell-Cell Fusion

2007 ◽  
Vol 81 (24) ◽  
pp. 13889-13903 ◽  
Author(s):  
Igor Beitia Ortiz de Zarate ◽  
Lilia Cantero-Aguilar ◽  
Magalie Longo ◽  
Clarisse Berlioz-Torrent ◽  
Flore Rozenberg
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Cell Surface ◽  
Cell Fusion ◽  
Virus Replication ◽  
Herpes Simplex Virus Type ◽  
Wild Type ◽  
Simplex Virus ◽  
Cell Cell

ABSTRACT The use of endocytic pathways by viral glycoproteins is thought to play various functions during viral infection. We previously showed in transfection assays that herpes simplex virus type 1 (HSV-1) glycoprotein B (gB) is transported from the cell surface back to the trans-Golgi network (TGN) and that two motifs of gB cytoplasmic tail, YTQV and LL, function distinctly in this process. To investigate the role of each of these gB trafficking signals in HSV-1 infection, we constructed recombinant viruses in which each motif was rendered nonfunctional by alanine mutagenesis. In infected cells, wild-type gB was internalized from the cell surface and concentrated in the TGN. Disruption of YTQV abolished internalization of gB during infection, whereas disruption of LL induced accumulation of internalized gB in early recycling endosomes and impaired its return to the TGN. The growth of both recombinants was moderately diminished. Moreover, the fusion phenotype of cells infected with the gB recombinants differed from that of cells infected with the wild-type virus. Cells infected with the YTQV-mutated virus displayed reduced cell-cell fusion, whereas giant syncytia were observed in cells infected with the LL-mutated virus. Furthermore, blocking gB internalization or impairing gB recycling to the cell surface, using drugs or a transdominant negative form of Rab11, significantly reduced cell-cell fusion. These results favor a role for endocytosis in virus replication and suggest that gB intracellular trafficking is involved in the regulation of cell-cell fusion.

scholarly journals Microtubules Are Dispensable for the Initial Pathogenic Development but Required for Long-Distance Hyphal Growth in the Corn Smut FungusUstilago maydis

2005 ◽  
Vol 16 (6) ◽  
pp. 2746-2758 ◽  
Author(s):  
Uta Fuchs ◽  
Isabel Manns ◽  
Gero Steinberg
Keyword(s):  
Cell Fusion ◽  
Hyphal Growth ◽  
Nuclear Migration ◽  
Structural Basis ◽  
Polarized Growth ◽  
Long Distance ◽  
Cycle Arrest ◽  
Similar Phenotype ◽  
A Cell ◽  
Cell Cell

Fungal pathogenicity often involves a yeast-to-hypha transition, but the structural basis for this dimorphism is largely unknown. Here we analyze the role of the cytoskeleton in early steps of pathogenic development in the corn pathogen Ustilago maydis. On the plant yeast-like cells recognize each other, undergo a cell cycle arrest, and form long conjugation hyphae, which fuse and give rise to infectious filaments. F-actin is essential for polarized growth at all these stages and for cell-cell fusion. Furthermore, F-actin participates in pheromone secretion, but not perception. Although U. maydis contains prominent tubulin arrays, microtubules are neither required for cell-cell recognition, nor for cell-cell fusion, and have only minor roles in morphogenesis of yeast-like cells. Without microtubules hyphae are formed, albeit at 60% reduced elongation rates, but they reach only ∼50 μm in length and the nucleus fails to migrate into the hypha. A similar phenotype is found in dynein mutants that have a nuclear migration defect and stop hyphal elongation at ∼50 μm. These results demonstrate that microtubules are dispensable for polarized growth during morphological transition, but become essential in long-distance hyphal growth, which is probably due to their role in nuclear migration.

scholarly journals Neurovirulent Murine Coronavirus JHM.SD Uses Cellular Zinc Metalloproteases for Virus Entry and Cell-Cell Fusion

2017 ◽  
Vol 91 (8) ◽  
Author(s):  
Judith M. Phillips ◽  
Tom Gallagher ◽  
Susan R. Weiss
Keyword(s):  
Cell Surface ◽  
Matrix Metalloproteinase ◽  
Serine Protease ◽  
Cell Fusion ◽  
Acid Ph ◽  
Endosomal Acidification ◽  
Zinc Metalloproteases ◽  
S Proteins ◽  
Cell Cell ◽  
Murine Coronavirus

ABSTRACT The coronavirus (CoV) S protein requires cleavage by host cell proteases to mediate virus-cell and cell-cell fusion. Many strains of the murine coronavirus mouse hepatitis virus (MHV) have distinct, S-dependent organ and tissue tropisms despite using a common receptor, suggesting that they employ different cellular proteases for fusion. In support of this hypothesis, we found that inhibition of endosomal acidification only modestly decreased entry, and overexpression of the cell surface protease TMPRSS2 greatly enhanced entry, of the highly neurovirulent MHV strain JHM.SD relative to their effects on the reference strain, A59. However, TMPRSS2 overexpression decreased MHV structural protein expression, release of infectious particles, and syncytium formation, and endogenous serine protease activity did not contribute greatly to infection. We therefore investigated the importance of other classes of cellular proteases and found that inhibition of matrix metalloproteinase (MMP)- and a disintegrin and metalloprotease (ADAM)-family zinc metalloproteases markedly decreased both entry and cell-cell fusion. Suppression of virus by metalloprotease inhibition varied among tested cell lines and MHV S proteins, suggesting a role for metalloprotease use in strain-dependent tropism. We conclude that zinc metalloproteases must be considered potential contributors to coronavirus fusion. IMPORTANCE The family Coronaviridae includes viruses that cause two emerging diseases of humans, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), as well as a number of important animal pathogens. Because coronaviruses depend on host protease-mediated cleavage of their S proteins for entry, a number of protease inhibitors have been proposed as antiviral agents. However, it is unclear which proteases mediate in vivo infection. For example, SARS-CoV infection of cultured cells depends on endosomal acid pH-dependent proteases rather than on the cell surface acid pH-independent serine protease TMPRSS2, but Zhou et al. (Antiviral Res 116:76–84, 2015, doi:10.1016/j.antiviral.2015.01.011) found that a serine protease inhibitor was more protective than a cathepsin inhibitor in SARS-CoV-infected mice. This paper explores the contributions of endosomal acidification and various proteases to coronavirus infection and identifies an unexpected class of proteases, the matrix metalloproteinase and ADAM families, as potential targets for anticoronavirus therapy.

scholarly journals Let curiosity lead you

2018 ◽  
Vol 29 (22) ◽  
pp. 2603-2605
Author(s):  
Elizabeth H. Chen
Keyword(s):  
Cell Fusion ◽  
Cell Biology ◽  
Multicellular Organisms ◽  
To Receive ◽  
Cell Cell

It is an incredible honor to receive the Woman in Cell Biology Mid-Career Award for Excellence in Research. My lab works on cell–cell fusion, an indispensable process in the conception, development, and physiology of multicellular organisms. In this essay, I reflect on my curiosity-led journey, which uncovered some unexpected mechanisms underlying cell–cell fusion.

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