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Review
. 2022 Oct 3;14(10):a041087.
doi: 10.1101/cshperspect.a041087.

The Burial: Clearance and Consequences

Douglas R Green  1
Affiliations
Review

The Burial: Clearance and Consequences

Douglas R Green. Cold Spring Harb Perspect Biol. .
No abstract available

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
Executioner caspases induce production of the “find-me” signal LPC. LPC, lysophosphatidylcholine; iPLA2, calcium-independent phospholipase A2; PC, phosphatidylcholine.
Figure 2.
Figure 2.
Plasma membrane scrambling and its detection in dying cells. Phosphatidylserine “scrambled” from the inner to the outer membrane can be detected by probes, such as fluorescently labeled annexin V. (Reprinted from Brumatti et al. 2008, ©2008 with permission from Elsevier.)
Figure 3.
Figure 3.
Detection of phosphatidylserine exposure by fluorescence-activated cell sorting (FACS). Cells were treated with the chemotherapy agent etoposide to induce apoptosis (± the caspase inhibitor zVAD-fmk) and then stained with annexin V (coupled with a fluorescent dye) and the vital dye 7-AAD. The fluorescence intensity of each cell is represented by a dot. Notice that the cell population becomes positive for annexin V before membrane integrity (measured by 7-AAD) is lost. This annexin V staining, and by implication phosphatidylserine exposure, is dependent on caspases, as treatment with the inhibitor zVAD largely prevented it. 7-AAD, 7-amino actinomycin D; zVAD, zVAD-fmk.
Figure 4.
Figure 4.
“Don't-eat-me” signals. These include the leukocyte surface antigen CD47, recognized by phagocyte cell-surface receptor SIRPα, and the homotypic interaction between CD31 molecules. SIRPα, signal-regulatory protein alpha.
Figure 5.
Figure 5.
A single tingible body macrophage (TBM) in a germinal center engulfing four apoptotic cells (arrows). (Reprinted from Hanayama et al. 2004, ©2004 with permission from AAAS.)
Figure 6.
Figure 6.
Bridge molecules are soluble molecules that bind to dying cells because of the changes in the plasma membrane. MBL, mannose-binding lectin; MFG-E8, lactadherin.
Figure 7.
Figure 7.
Complement components C1q and C3b can also bind to dying cells to act as bridge molecules.
Figure 8.
Figure 8.
Recognition of phosphatidylserine (PS), exposed on dying cells, by phagocytes occurs either directly (e.g., for BAI1, stabilin 2, TIM4) or indirectly through bridge molecules (e.g., for MER, integrins).
Figure 9.
Figure 9.
Scavenger receptors recognize dying cells expressing, for example, altered carbohydrates and exposed phosphatidylserine.
Figure 10.
Figure 10.
The array of “bind-me” receptors that can directly, or indirectly through bridge molecules, bind to dying cells.
Figure 11.
Figure 11.
Recognition receptors CED1 and CED7 in nematodes. CED7 is important in both the dying and the engulfing cells, whereas CED1 is important in the engulfing cell. CED1 can bind to a bridging molecule, TTR-52, which recognizes phosphatidylserine and is required for clearance of dying cells. There is at least one additional receptor (not illustrated) involved in recognition and engulfment of dying cells.
Figure 12.
Figure 12.
The Drosophila Croquemort mutant has defects in engulfment of dying cells. Here, phagocytic cells (green, with white stars) take up small dying cells (red) in wild-type flies (left) but not in mutants unable to express Croquemort (right). (Franc et al. 1999.)
Figure 13.
Figure 13.
Two pathways converge on the Ras-related protein CED10 (Rac1) to induce actin reorganization and phagocytosis. Although one pathway is linked to CED1 and CED7, the other pathway is initiated in the nematode Caenorhabditis elegans by an unknown receptor.
Figure 14.
Figure 14.
CED1 (nematodes) and stabilin-2 (mammals) engage an adapter molecule, CED6 or GULP, respectively, following recognition of dying cells. CED6/GULP activates CED10/RAC1 by an unknown mechanism.
Figure 15.
Figure 15.
BAI1 in mammals, and an unknown receptor in nematodes, engage a signaling complex (comprising CRKII–DOCK180–ELMO–Rac1 or CED2–CED5–CED12–CED10, respectively) following recognition of dying cells.
Figure 16.
Figure 16.
The phosphatidylserine-binding receptor BAI1 (and other receptors) in mammals induce the GDP–GTP exchange factor TRIO, which activates the small GTPase RHOG, converting it to the GTP-bound active form.
Figure 17.
Figure 17.
ELMO recruits DOCK180, which binds to RAC1, leading to the activation of this small GTPase. Engulfment by the phagocyte then proceeds.
Figure 18.
Figure 18.
The phagosome and degradation. The phagocyte envelops the dying cell, forming an internal phagosome that, on rearrangement of the actin cytoskeleton and fusion with a lysosome, forms a phagolysosome, where disposal of the dying cell takes place.
Figure 19.
Figure 19.
Uptake of dying cells induces cholesterol management. Activation of the peroxisome proliferator-activated receptor γ (PPARγ) induces the expression of the nuclear oxysterols receptor LXR-alpha (NR1H3), which in turn induces the expression of a cholesterol transporter operating at the plasma membrane.
Figure 20.
Figure 20.
Apoptotic cells can inhibit inflammation. Mer, tyrosine-protein kinase Mer; PPAR γ, peroxisome proliferator-activated receptor γ; SOCS1, suppressor of cytokine signaling 1; TGF-β, transforming growth factor beta; TLR, Toll-like receptor.
Figure 21.
Figure 21.
Neutrophils swarm to sites of cell damage. A single cell was damaged by laser light (dashed circle). Within seconds, the neutrophils (red) swarm to the site, followed by macrophages (green). The elapsed time is shown (minutes:seconds).
Figure 22.
Figure 22.
The high-mobility group protein B1 (HMGB1) in immunity versus tolerance. Apoptotic cells, unlike necrotic cells, end up oxidizing HMGB1, preventing it from promoting an immune response.
Figure 23.
Figure 23.
Dying cells influence T-cell functional differentiation. TGF-β, transforming growth factor beta.
Figure 24.
Figure 24.
LC3-associated phagocytosis occurs on engulfment of dying cells. As the phagosome forms, an unknown signal is generated that recruits a complex containing beclin-1 and the phosphoinositide 3-kinase VPS34, and other molecules distinct from those involved in autophagy. As a result, the ligase complex is recruited and LC3 is conjugated to lipids in the phagosome membrane. This facilitates fusion with lysosomes and the degradation of the corpse.
Figure 25.
Figure 25.
LC3-associated phagocytosis occurs on engulfment of dying cells. Macrophages expressing an LC3 fused to green-fluorescent protein (GFP) were cocultured with cells (stained red) that were dying by means of different mechanisms. Note the ring of green LC3 around the corpse-containing phagosomes. (Provided by Jennifer Martinez and Clifford Guy, Department of Immunology, St. Jude Children's Research Hospital.)
Figure 26.
Figure 26.
LE bodies. These are apoptotic cells in the circulation and are diagnostic of systemic lupus erythematosus (SLE). (Reprinted from Holman 1951, with permission from BMJ Publishing Group Ltd.)
Figure 27.
Figure 27.
Pathways and molecules of cell death by entosis. LAP, LC3-associated phagocytosis. (Michael Overholter, unpublished.)
Figure 28.
Figure 28.
Caspase activation promotes compensatory proliferation in the fruit fly Drosophila. DIAP1, death-associated inhibitor of apoptosis 1; Dpp, Decapentaplegic.
See this image and copyright information in PMC

References

    1. Green DR. 2022a. Nonapoptotic cell death pathways. Cold Spring Harb Perspect Biol 10.1101/cshperspect.a041079 - DOI - PMC - PubMed
    1. Green DR. 2022b. Inflammasomes and other caspase-activation platforms. Cold Spring Harb Perspect Biol 10.1101/cshperspect.a041061 - DOI - PMC - PubMed
    1. Green DR. 2022c. Caspases and their substrates. Cold Spring Harb Perspect Biol 10.1101/cshperspect.a041012 - DOI - PMC - PubMed
    1. Green DR. 2022d. Cell death in development. Cold Spring Harb Perspect Biol 10.1101/cshperspect.a041095 - DOI - PMC - PubMed
    1. Green DR. 2022e. Cell death and cancer. Cold Spring Harb Perspect Biol 10.1101/cshperspect.a041103 - DOI - PubMed

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