SLI-1 Cbl Inhibits the Engulfment of Apoptotic Cells in C. elegans through a Ligase-Independent Function

Autophagosomes are double-membrane intracellular vesicles that degrade protein aggregates, intracellular organelles, and other cellular components. In the nematode Caenorhabditis elegans, 113 somatic cells undergo apoptosis during embryogenesis and are engulfed and degraded by their neighboring cells. We discovered a novel role of autophagosomes in facilitating the degradation of apoptotic cells in C. elegans embryos using a real-time imaging technique. Specifically, double-membrane autophagosomes in engulfing cells are recruited to the surfaces of phagosomes containing apoptotic cells and subsequently fuse to phagosomes, allowing the inner membrane to enter the phagosomal lumen. Mutants defective in the production of autophagosomes display significant delays in the degradation of apoptotic cells, demonstrating the important contribution of autophagosomes to this process. The signaling pathway led by the phagocytic receptor CED-1, CED-1s adaptor CED-6, and the large GTPase dynamin (DYN-1) promote 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. Our findings reveal that, unlike the single-membrane, LC3- associated phagocytosis (LAP) vesicles reported for mammalian phagocytes, canonical autophagosomes function in 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 factors that initiate this crosstalk.

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C. elegans mitochondrial factor WAH-1 promotes phosphatidylserine externalization in apoptotic cells through phospholipid scramblase SCRM-1

Nature Cell Biology ◽

10.1038/ncb1574 ◽

2007 ◽

Vol 9 (5) ◽

pp. 541-549 ◽

Cited By ~ 85

Author(s):

Xiaochen Wang ◽

Jin Wang ◽

Keiko Gengyo-Ando ◽

Lichuan Gu ◽

Chun-Ling Sun ◽

...

Keyword(s):

Apoptotic Cells ◽

C Elegans ◽

Phospholipid Scramblase ◽

Phosphatidylserine Externalization

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

eLife ◽

10.7554/elife.72466 ◽

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.

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Faculty Opinions recommendation of C. elegans Dynamin mediates the signaling of phagocytic receptor CED-1 for the engulfment and degradation of apoptotic cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1032684.374474 ◽

2006 ◽

Author(s):

Barbara Conradt

Keyword(s):

Apoptotic Cells ◽

C Elegans

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The amino acid transporter SLC-36.1 cooperates with PtdIns3P 5-kinase to control phagocytic lysosome reformation

The Journal of Cell Biology ◽

10.1083/jcb.201901074 ◽

2019 ◽

Vol 218 (8) ◽

pp. 2619-2637 ◽

Cited By ~ 3

Author(s):

Qiwen Gan ◽

Xin Wang ◽

Qian Zhang ◽

Qiuyuan Yin ◽

Youli Jian ◽

...

Keyword(s):

Amino Acid ◽

Caenorhabditis Elegans ◽

Amino Acid Transporter ◽

Apoptotic Cells ◽

Phagosome Maturation ◽

Genetic Pathway ◽

C Elegans ◽

Acid Transporter ◽

Cell Corpse ◽

Cell Corpse Clearance

Phagocytic removal of apoptotic cells involves formation, maturation, and digestion of cell corpse–containing phagosomes. The retrieval of lysosomal components following phagolysosomal digestion of cell corpses remains poorly understood. Here we reveal that the amino acid transporter SLC-36.1 is essential for lysosome reformation during cell corpse clearance in Caenorhabditis elegans embryos. Loss of slc-36.1 leads to formation of phagolysosomal vacuoles arising from cell corpse–containing phagosomes. In the absence of slc-36.1, phagosome maturation is not affected, but the retrieval of lysosomal components is inhibited. Moreover, loss of PPK-3, the C. elegans homologue of the PtdIns3P 5-kinase PIKfyve, similarly causes accumulation of phagolysosomal vacuoles that are defective in phagocytic lysosome reformation. SLC-36.1 and PPK-3 function in the same genetic pathway, and they directly interact with one another. In addition, loss of slc-36.1 and ppk-3 causes strong defects in autophagic lysosome reformation in adult animals. Our findings thus suggest that the PPK-3–SLC-36.1 axis plays a central role in both phagocytic and autophagic lysosome formation.

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

Molecular Biology of the Cell ◽

10.1091/mbc.e14-01-0015 ◽

2014 ◽

Vol 25 (13) ◽

pp. 2071-2083 ◽

Cited By ~ 16

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.

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The CHORD protein CHP-1 regulates EGF receptor trafficking and signaling in C. elegans and in human cells

10.1101/745984 ◽

2019 ◽

Author(s):

Andrea Haag ◽

Michael Walser ◽

Adrian Henggeler ◽

Alex Hajnal

Keyword(s):

Intracellular Trafficking ◽

Egf Receptor ◽

Mapk Signaling ◽

Human Cells ◽

Receptor Trafficking ◽

Independent Function ◽

Vulval Development ◽

C Elegans ◽

Downstream Signaling

AbstractThe intracellular trafficking of growth factor receptors determines the activity of their downstream signaling pathways. The putative co-chaperone CHP-1 acts as a regulator of EGFR trafficking during C.elegans vulval development. Loss of chp-1 causes the retention of the EGFR in the ER and decreased MAPK signaling. CHP-1 functions specifically, as the localization of other receptors is unaltered in chp-1(lf) mutants, and inhibiting other co-chaperones does not affect EGFR localization. The role of CHP-1 during EGFR trafficking is conserved in humans. Analogous to C.elegans, the response of CHP-1-deficient human cells to EGF stimulation is attenuated, the EGFR accumulates in the ER and ERK2 activity is decreased. Although CHP-1 has been proposed to act as a co-chaperone for HSP90, our data indicate an HSP90-independent function of CHP-1. The identification of CHP-1 as a regulator of EGFR trafficking opens the possibility to identify small molecule chaperone inhibitors targeting the EGFR pathway with increased selectivity.

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