scholarly journals Spatial Control of Draper Receptor Signaling Initiates Apoptotic Cell Engulfment

2017 ◽  
Author(s):  
Adam P. Williamson ◽  
Ronald D. Vale
Keyword(s):  
T Cell Receptor ◽  
Apoptotic Cell ◽  
Cell Receptor ◽  
Apoptotic Cells ◽  
S2 Cells ◽  
Triggering Mechanism ◽  
Spatial Control ◽  
Drosophila S2 Cells ◽  
Similarities And Differences ◽  
Cell Engulfment

AbstractThe engulfment of apoptotic cells is essential for tissue homeostasis and responding to damage. Engulfment is mediated by receptors that recognize ligands exposed on apoptotic cells, such as phosphatidylserine (PS). Here, we convert Drosophila S2 cells into proficient phagocytes by transfecting the Draper engulfment receptor and replacing apoptotic cells with PS-coated beads. We show that PS-ligated Draper forms microclusters that exclude a bulky transmembrane phosphatase and recruit phosphotyrosine binding proteins, revealing a triggering mechanism similar to the T cell receptor (TCR). Analogous to the TCR, Draper’s extracellular domain and PS can be replaced with FRB and FKBP respectively, resulting in a rapamycin-inducible engulfment system. However, in contrast to the TCR, we show that localized signaling at Draper microclusters results in time-dependent depolymerization of actin filaments. Collectively, our results reveal mechanistic similarities and differences between the receptors involved in apoptotic corpse clearance and mammalian immunity and demonstrate that engulfment can be reprogrammed towards non-native targets.Condensed titleSpatial Control of Engulfment Signaling

scholarly journals Spatial control of Draper receptor signaling initiates apoptotic cell engulfment

2018 ◽  
Vol 217 (11) ◽  
pp. 3977-3992 ◽  
Author(s):  
Adam P. Williamson ◽  
Ronald D. Vale
Keyword(s):  
Apoptotic Cell ◽  
Cell Receptor ◽  
Effector Proteins ◽  
Apoptotic Cells ◽  
S2 Cells ◽  
Triggering Mechanism ◽  
Spatial Control ◽  
Drosophila Melanogaster S2 Cells ◽  
Similarities And Differences ◽  
Cell Engulfment

The engulfment of apoptotic cells is essential for tissue homeostasis and recovering from damage. Engulfment is mediated by receptors that recognize ligands exposed on apoptotic cells such as phosphatidylserine (PS). In this study, we convert Drosophila melanogaster S2 cells into proficient phagocytes by transfecting the Draper engulfment receptor and replacing apoptotic cells with PS-coated beads. Similar to the T cell receptor (TCR), PS-ligated Draper forms dynamic microclusters that recruit cytosolic effector proteins and exclude a bulky transmembrane phosphatase, consistent with a kinetic segregation-based triggering mechanism. However, in contrast with the TCR, localized signaling at Draper microclusters results in time-dependent depletion of actin filaments, which facilitates engulfment. The Draper–PS extracellular module can be replaced with FRB and FKBP, respectively, resulting in a rapamycin-inducible engulfment system that can be programmed toward defined targets. Collectively, our results reveal mechanistic similarities and differences between the receptors involved in apoptotic corpse clearance and mammalian immunity and demonstrate that engulfment can be reprogrammed toward nonnative targets.

scholarly journals Two Alternative Mechanisms That Regulate the Presentation of Apoptotic Cell Engulfment Signal in Caenorhabditis elegans

2007 ◽  
Vol 18 (8) ◽  
pp. 3180-3192 ◽  
Author(s):  
Victor Venegas ◽  
Zheng Zhou
Keyword(s):  
Caenorhabditis Elegans ◽  
Abc Transporter ◽  
Germ Cells ◽  
Mammalian Cells ◽  
Developmental Stages ◽  
Apoptotic Cell ◽  
Somatic Cells ◽  
Apoptotic Cells ◽  
Phospholipid Scramblase ◽  
Cell Engulfment

Phosphatidylserine exposed on the surface of apoptotic mammalian cells is considered an “eat-me” signal that attracts phagocytes. The generality of using phosphatidylserine as a clearance signal for apoptotic cells in animals and the regulation of this event remain uncertain. Using ectopically expressed mouse MFG-E8, a secreted phosphatidylserine-binding protein, we detected specific exposure of phosphatidylserine on the surface of apoptotic cells in Caenorhabditis elegans. Masking the surface phosphatidylserine inhibits apoptotic cell engulfment. CED-7, an ATP-binding cassette (ABC) transporter, is necessary for the efficient exposure of phosphatidylserine on apoptotic somatic cells, and for the recognition of these cells by phagocytic receptor CED-1. Alternatively, phosphatidylserine exposure on apoptotic germ cells is not CED-7 dependent, but instead requires phospholipid scramblase PLSC-1, a homologue of mammalian phospholipid scramblases. Moreover, deleting plsc-1 results in the accumulation of apoptotic germ cells but not apoptotic somatic cells. These observations suggest that phosphatidylserine might be recognized by CED-1 and act as a conserved eat-me signal from nematodes to mammals. Furthermore, the two different biochemical activities used in somatic cells (ABC transporter) and germ cells (phospholipid scramblase) suggest an increased complexity in the regulation of phosphatidylserine presentation in response to apoptotic signals in different tissues and during different developmental stages.

scholarly journals 9-cis retinoic acid inhibition of activation-induced apoptosis is mediated via regulation of fas ligand and requires retinoic acid receptor and retinoid X receptor activation.

1995 ◽  
Vol 15 (10) ◽  
pp. 5576-5585 ◽  
Author(s):  
R P Bissonnette ◽  
T Brunner ◽  
S B Lazarchik ◽  
N J Yoo ◽  
M F Boehm ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
T Cell ◽  
T Cell Receptor ◽  
Target Genes ◽  
Fas Ligand ◽  
Apoptotic Cell ◽  
Cell Receptor ◽  
Receptor Activation ◽  
Retinoid Receptor ◽  
Induced Apoptosis

T-cell hybridomas, thymocytes, and T cells can be induced to undergo apoptotic cell death by activation through the T-cell receptor. This process requires macromolecular synthesis and thus gene expression, and it has been shown to be influenced by factors regulating transcription. Recently, activation, T-cell hybridomas rapidly express the Fas/CD95 receptor and its ligand, Fas ligand (FasL), which interact to transduce the death signal in the activated cell. Retinoids, the active metabolites of vitamin A, modulate expression of specific target genes by binding to two classes of intracellular receptors, retinoic acid receptors (RARs) and retinoid X receptors (RXRs). They are potent modulators of apoptosis in a number of experimental models, and they have been shown to inhibit activation-induced apoptosis in T-cell hybridomas and thymocytes. Particularly effective is the prototypic pan-agonist 9-cis retinoic acid (9-cis RA), which has high affinity for both RARs and RXRs. We report here that 9-cis RA inhibits T-cell receptor-mediated apoptosis in T-cell hybridomas by blocking the expression of Fas ligand following activation. This inhibition appears to be at the level of FasL mRNA, with the subsequent failure to express cell surface FasL. RAR-selective (TTNPB) or RXR-selective (LG100268) ligands alone were considerably less potent than RAR-RXR pan-agonists. However, the addition of both RAR- and RXR-selective ligands was as effective as the addition of 9-cis RA alone. The demonstrates that the inhibitory effect requires the ligand-mediated activation of both retinoid receptor signaling pathways.

Incomplete T-cell receptor–β peptides target the mitochondrion and induce apoptosis

Blood ◽  
2009 ◽  
Vol 113 (15) ◽  
pp. 3530-3541 ◽  
Author(s):  
Nir Shani ◽  
Hila Rubin-Lifshitz ◽  
Yifat Peretz-Cohen ◽  
Ketty Shkolnik ◽  
Vera Shinder ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Transmembrane Domain ◽  
Apoptotic Cell ◽  
Function Analysis ◽  
Alternative Pathway ◽  
Cell Receptor ◽  
C Terminus ◽  
Specific Localization ◽  
Induced Structure

Abstract The default pathway of cell-surface T-cell receptor (TCR) complex formation, and the subsequent transport to the membrane, is thought to entail endoplasmic reticulum (ER) localization followed by proteasome degradation of the unassembled chains. We show herein an alternative pathway: short, incomplete peptide versions of TCRβ naturally occur in the thymus. Such peptides, which have minimally lost the leader sequence or have been massively truncated, leaving only the very C terminus intact, are sorted preferentially to the mitochondrion. As a consequence of the mitochondrial localization, apoptotic cell death is induced. Structure function analysis showed that both the specific localization and induction of apoptosis depend on the transmembrane domain (TMD) and associated residues at the COOH-terminus of TCR. Truncated forms of TCR, such as the short peptides that we detected in the thymus, may be products of protein degradation within thymocytes. Alternatively, they may occur through the translation of truncated mRNAs resulting from unfruitful rearrangement or from germline transcription. It is proposed that mitochondria serve as a subcellular sequestration site for incomplete TCR molecules.

scholarly journals Immature thymocytes become sensitive to calcium-mediated apoptosis with the onset of CD8, CD4, and the T cell receptor expression: a role for bcl-2?

1993 ◽  
Vol 178 (5) ◽  
pp. 1745-1751 ◽  
Author(s):  
S Andjelić ◽  
N Jain ◽  
J Nikolić-Zugić
Keyword(s):  
Cell Death ◽  
T Cell ◽  
T Cell Receptor ◽  
Apoptotic Cell ◽  
Calcium Ionophore ◽  
Cell Receptor ◽  
Receptor Expression ◽  
Clonal Deletion ◽  
Induced Apoptosis ◽  
Precursor Activity

During intrathymic negative selection by clonal deletion, crosslinking of the T cell receptor (TCR) induces cell death by delivering an apoptotic signal(s) to the nucleus along a calcium-dependent pathway. We investigated the reactivity of early precursor-containing thymocytes to Ca(2+)-induced signals, and discovered a breakpoint in their sensitivity to calcium-mediated cell death (CMCD). CD25+CD8-4- TCR- (triple negative [TN]) thymocytes stimulated with a calcium ionophore maintain their viability and precursor activity. By contrast, their immediate progeny, CD25-CD8lo4loTCR alpha beta lo (triple low [TL]) cells react to calcium elevation by abrogation of precursor activity and apoptotic cell death. This developmental difference is specific for CMCD, since both CD25+TN and CD25-TL cells are susceptible to steroid-induced apoptosis. The presence of bcl-2 mRNA correlates directly to the resistance to CMCD-CD25+ TN cells express it and CD25-TL cells do not. These experiments show that thymocytes become sensitive to Ca(2+)-induced apoptosis as soon as they begin to express molecules that mediate thymic selection, and suggest that a concomitant downregulation of bcl-2 may mediate this phenomenon.

scholarly journals Oxidized phosphatidylserine–CD36 interactions play an essential role in macrophage-dependent phagocytosis of apoptotic cells

2006 ◽  
Vol 203 (12) ◽  
pp. 2613-2625 ◽  
Author(s):  
Michael E. Greenberg ◽  
Mingjiang Sun ◽  
Renliang Zhang ◽  
Maria Febbraio ◽  
Roy Silverstein ◽  
...  
Keyword(s):  
Molecular Species ◽  
Essential Role ◽  
Apoptotic Cell ◽  
Scavenger Receptor ◽  
Apoptotic Cells ◽  
Class B ◽  
Oxidized Phosphatidylcholine ◽  
Cell Engulfment

The phagocytosis of apoptotic cells within an organism is a critical terminal physiological process in programmed cell death. Evidence suggests that apoptotic cell engulfment and removal by macrophages is facilitated by phosphatidylserine (PS) displayed at the exofacial surface of the plasma membrane; however, neither the macrophage receptors responsible for PS recognition, nor characterization of the PS molecular species potentially involved, have been clearly defined. We show that the class B scavenger receptor CD36 plays an essential role in macrophage clearance of apoptotic cells in vivo. Further, macrophage recognition of apoptotic cells via CD36 is shown to occur via interactions with membrane-associated oxidized PS (oxPS) and, to a lesser extent, oxidized phosphatidylcholine, but not nonoxidized PS molecular species. Mass spectrometry analyses of oxPS species identify structures of candidate ligands for CD36 in apoptotic membranes that may facilitate macrophage recognition. Collectively, these results identify oxPS–CD36 interactions on macrophages as potential participants in a broad range of physiologic processes where macrophage-mediated engulfment of apoptotic cells is involved.

scholarly journals Suppressive Role of B Cells in Chronic Colitis of  T Cell Receptor α Mutant Mice

1997 ◽  
Vol 186 (10) ◽  
pp. 1749-1756 ◽  
Author(s):  
Atsushi Mizoguchi ◽  
Emiko Mizoguchi ◽  
R. Neal Smith ◽  
Frederic I. Preffer ◽  
Atul K. Bhan
Keyword(s):  
T Cell ◽  
B Cells ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Mutant Mice ◽  
Apoptotic Cells ◽  
Chronic Colitis ◽  
Recombination Activating Gene ◽  
Rag 1

The role of antibodies (Abs) in the development of chronic colitis in T cell receptor (TCR)-α−/− mice was explored by creating double mutant mice (TCR-α−/− × immunoglobulin (Ig)μ−/−), which lack B cells. TCR-α−/− × Igμ−/− mice spontaneously developed colitis at an earlier age, and the colitis was more severe than in TCR-α−/− mice. Colitis was induced in recombination-activating gene-1 (RAG-1−/−) mice by the transfer of mesenteric lymph node (MLN) cells from TCR-α−/− × Igμ−/− mice. When purified B cells from TCR-α−/− mice were mixed with MLN cells before cell transfer, colitis did not develop in RAG-1−/− mice. Administration of the purified Ig from TCR-α−/− mice and a mixture of monoclonal autoAbs reactive with colonic epithelial cells led to attenuation of colitis in TCR-α−/− × Igμ−/− mice. Apoptotic cells were increased in the colon, MLN, and spleen of TCR-α−/− × Igμ−/− mice as compared to Igμ−/− mice and TCR-α−/− mice. Administration of the purified Ig from TCR-α−/− mice into TCR-α−/− × Igμ−/− mice led to decrease in the number of apoptotic cells. These findings suggest that although B cells are not required for the initiation of colitis, B cells and Igs (autoAbs) can suppress colitis, presumably by affecting the clearance of apoptotic cells.

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