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 Genetic control of programmed cell death in the Caenorhabditis elegans hermaphrodite germline

Development ◽  
1999 ◽  
Vol 126 (5) ◽  
pp. 1011-1022 ◽  
Author(s):  
T.L. Gumienny ◽  
E. Lambie ◽  
E. Hartwieg ◽  
H.R. Horvitz ◽  
M.O. Hengartner
Keyword(s):  
Cell Death ◽  
Caenorhabditis Elegans ◽  
Germ Cell ◽  
Somatic Cell ◽  
Cell Fate ◽  
Germ Cells ◽  
Mapk Pathway ◽  
Apoptotic Cell ◽  
C Elegans ◽  
Pathway Activation

Development of the nematode Caenorhabditis elegans is highly reproducible and the fate of every somatic cell has been reported. We describe here a previously uncharacterized cell fate in C. elegans: we show that germ cells, which in hermaphrodites can differentiate into sperm and oocytes, also undergo apoptotic cell death. In adult hermaphrodites, over 300 germ cells die, using the same apoptotic execution machinery (ced-3, ced-4 and ced-9) as the previously described 131 somatic cell deaths. However, this machinery is activated by a distinct pathway, as loss of egl-1 function, which inhibits somatic cell death, does not affect germ cell apoptosis. Germ cell death requires ras/MAPK pathway activation and is used to maintain germline homeostasis. We suggest that apoptosis eliminates excess germ cells that acted as nurse cells to provide cytoplasmic components to maturing oocytes.

scholarly journals Autophagosomes fuse to phagosomes and facilitate the degradation of apoptotic cells in Caenorhabditis elegans

eLife ◽  
2022 ◽  
Vol 11 ◽  
Author(s):  
Omar Peña-Ramos ◽  
Lucia Chiao ◽  
Xianghua Liu ◽  
Xiaomeng Yu ◽  
Tianyou Yao ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Apoptotic Cell ◽  
Adaptor Protein ◽  
Small Gtpase ◽  
Apoptotic Cells ◽  
Phagosome Maturation ◽  
Double Membrane ◽  
C Elegans ◽  
Intracellular Organelles ◽  
Cellular Components

Autophagosomes are double-membrane intracellular vesicles that degrade protein aggregates, intracellular organelles, and other cellular components. During the development of the nematode Caenorhabditis elegans, many somatic and germ cells undergo apoptosis. These cells are engulfed and degraded by their neighboring cells. We discovered a novel role of autophagosomes in facilitating the degradation of apoptotic cells using a real-time imaging technique. Specifically, the double-membrane autophagosomes in engulfing cells are recruited to the surfaces of phagosomes containing apoptotic cells and subsequently fuse to phagosomes, allowing the inner vesicle to enter the phagosomal lumen. Mutants defective in the production of autophagosomes display significant defects in the degradation of apoptotic cells, demonstrating the importance of autophagosomes to this process. The signaling pathway led by the phagocytic receptor CED-1, the adaptor protein CED-6, and the large GTPase dynamin (DYN-1) promotes the recruitment of autophagosomes to phagosomes. Moreover, the subsequent fusion of autophagosomes with phagosomes requires the functions of the small GTPase RAB-7 and the HOPS complex components. Further observations suggest that autophagosomes provide apoptotic cell-degradation activities in addition to and in parallel of lysosomes. Our findings reveal that, unlike the single-membrane, LC3-associated phagocytosis (LAP) vesicles reported for mammalian phagocytes, the canonical double-membrane autophagosomes facilitate the clearance of C. elegans apoptotic cells. These findings add autophagosomes to the collection of intracellular organelles that contribute to phagosome maturation, identify novel crosstalk between the autophagy and phagosome maturation pathways, and discover the upstream signaling molecules that initiate this crosstalk.

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 The lysosomal cathepsin protease CPL-1 plays a leading role in phagosomal degradation of apoptotic cells in Caenorhabditis elegans

2014 ◽  
Vol 25 (13) ◽  
pp. 2071-2083 ◽  
Author(s):  
Meng Xu ◽  
Yubing Liu ◽  
Liyuan Zhao ◽  
Qiwen Gan ◽  
Xiaochen Wang ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Apoptotic Cell ◽  
Cell Types ◽  
Apoptotic Cells ◽  
C Elegans ◽  
Lysosomal Protease ◽  
Leading Role ◽  
Lysosomal Proteases ◽  
Cell Corpse

During programmed cell death, the clearance of apoptotic cells is achieved by their phagocytosis and delivery to lysosomes for destruction in engulfing cells. However, the role of lysosomal proteases in cell corpse destruction is not understood. Here we report the identification of the lysosomal cathepsin CPL-1 as an indispensable protease for apoptotic cell removal in Caenorhabditis elegans. We find that loss of cpl-1 function leads to strong accumulation of germ cell corpses, which results from a failure in degradation rather than engulfment. CPL-1 is expressed in a variety of cell types, including engulfment cells, and its mutation does not affect the maturation of cell corpse–containing phagosomes, including phagosomal recruitment of maturation effectors and phagosome acidification. Of importance, we find that phagosomal recruitment and incorporation of CPL-1 occurs before digestion of cell corpses, which depends on factors required for phagolysosome formation. Using RNA interference, we further examine the role of other candidate lysosomal proteases in cell corpse clearance but find that they do not obviously affect this process. Collectively, these findings establish CPL-1 as the leading lysosomal protease required for elimination of apoptotic cells in C. elegans.

scholarly journals Arl8/ARL-8 functions in apoptotic cell removal by mediating phagolysosome formation inCaenorhabditis elegans

2013 ◽  
Vol 24 (10) ◽  
pp. 1584-1592 ◽  
Author(s):  
Ayaka Sasaki ◽  
Isei Nakae ◽  
Maya Nagasawa ◽  
Keisuke Hashimoto ◽  
Fumiko Abe ◽  
...  
Keyword(s):  
Germ Cells ◽  
Apoptotic Cell ◽  
Small Gtpase ◽  
Tissue Homeostasis ◽  
Apoptotic Cells ◽  
Loss Of Function ◽  
Efficient Removal ◽  
Phagosomal Maturation ◽  
Late Stages

Efficient clearance of apoptotic cells by phagocytes is important for development, tissue homeostasis, and the prevention of autoimmune responses. Phagosomes containing apoptotic cells undergo acidification and mature from Rab5-positive early to Rab7-positive late stages. Phagosomes finally fuse with lysosomes to form phagolysosomes, which degrade apoptotic cells; however, the molecular mechanism underlying phagosome–lysosome fusion is not fully understood. Here we show that the Caenorhabditis elegans Arf-like small GTPase Arl8 (ARL-8) is involved in phagolysosome formation and is required for the efficient removal of apoptotic cells. Loss of function of arl-8 results in the accumulation of apoptotic germ cells. Both the engulfment of the apoptotic cells by surrounding somatic sheath cells and the phagosomal maturation from RAB-5- to RAB-7-positive stages occur in arl-8 mutants. However, the phagosomes fail to fuse with lysosomes in the arl-8 mutants, leading to the accumulation of RAB-7-positive phagosomes and the delayed degradation of apoptotic cells. ARL-8 localizes primarily to lysosomes and physically interacts with the homotypic fusion and protein sorting complex component VPS-41. Collectively our findings reveal that ARL-8 facilitates apoptotic cell removal in vivo by mediating phagosome–lysosome fusion during phagocytosis.

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 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 Lysosome Biogenesis Mediated by vps-18 Affects Apoptotic Cell Degradation in Caenorhabditis elegans

2009 ◽  
Vol 20 (1) ◽  
pp. 21-32 ◽  
Author(s):  
Hui Xiao ◽  
Didi Chen ◽  
Zhou Fang ◽  
Jing Xu ◽  
Xiaojuan Sun ◽  
...  
Keyword(s):  
Cell Death ◽  
Caenorhabditis Elegans ◽  
Programmed Cell Death ◽  
Direct Evidence ◽  
Apoptotic Cell ◽  
Apoptotic Cells ◽  
Lysosome Biogenesis ◽  
Cell Corpse ◽  
Lysosomal Protein

Appropriate clearance of apoptotic cells (cell corpses) is an important step of programmed cell death. Although genetic and biochemical studies have identified several genes that regulate the engulfment of cell corpses, how these are degraded after being internalized in engulfing cell remains elusive. Here, we show that VPS-18, the Caenorhabditis elegans homologue of yeast Vps18p, is critical to cell corpse degradation. VPS-18 is expressed and functions in engulfing cells. Deletion of vps-18 leads to significant accumulation of cell corpses that are not degraded properly. Furthermore, vps-18 mutation causes strong defects in the biogenesis of endosomes and lysosomes, thus affecting endosomal/lysosomal protein degradation. Importantly, we demonstrate that phagosomes containing internalized cell corpses are unable to fuse with lysosomes in vps-18 mutants. Our findings thus provide direct evidence for the important role of endosomal/lysosomal degradation in proper clearance of apoptotic cells during programmed cell death.

scholarly journals Presumptive TRP channel CED-11 promotes cell volume decrease and facilitates degradation of apoptotic cells in Caenorhabditis elegans

2017 ◽  
Vol 114 (33) ◽  
pp. 8806-8811 ◽  
Author(s):  
Kaitlin Driscoll ◽  
Gillian M. Stanfield ◽  
Rita Droste ◽  
H. Robert Horvitz
Keyword(s):  
Caenorhabditis Elegans ◽  
Cell Survival ◽  
Cell Volume ◽  
Transient Receptor Potential ◽  
Apoptotic Cell ◽  
Morphological Changes ◽  
Receptor Potential ◽  
Death Process ◽  
Apoptotic Cells ◽  
Caspase Cleavage

Apoptotic cells undergo a series of morphological changes. These changes are dependent on caspase cleavage of downstream targets, but which targets are significant and how they facilitate the death process are not well understood. In Caenorhabditis elegans an increase in the refractility of the dying cell is a hallmark morphological change that is caspase dependent. We identify a presumptive transient receptor potential (TRP) cation channel, CED-11, that acts in the dying cell to promote the increase in apoptotic cell refractility. CED-11 is required for multiple other morphological changes during apoptosis, including an increase in electron density as visualized by electron microscopy and a decrease in cell volume. In ced-11 mutants, the degradation of apoptotic cells is delayed. Mutation of ced-11 does not cause an increase in cell survival but can enhance cell survival in other cell-death mutants, indicating that ced-11 facilitates the death process. In short, ced-11 acts downstream of caspase activation to promote the shrinkage, death, and degradation of apoptotic cells.

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