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Review
. 2022 Feb 1;14(2):a041053.
doi: 10.1101/cshperspect.a041053.

The Death Receptor Pathway of Apoptosis

Douglas R Green  1
Affiliations
Review

The Death Receptor Pathway of Apoptosis

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

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
The death receptors and their ligands. Several names for each are shown. Of all of the ligands, only APP is not a member of the tumor necrosis factor (TNF) family.
Figure 2.
Figure 2.
Death receptors and death ligands are trimeric. Shown are two views of the structure of tumor necrosis factor (TNF; green) bound to the extracellular regions of the TNF receptor (TNFR1, blue). (PDB 1TNR [Banner et al. 1993].)
Figure 3.
Figure 3.
Ribbon diagrams of the representative structures of distinct death folds. DD, death domain; CARD, caspase-recruitment domain; PyD, pyrin domain; DED, death effector domain.
Figure 4.
Figure 4.
The structure of the CD95 receptor death domain (DD) binding to the DD of the FAS-associated death domain protein (FADD) viewed from top, side, and underside. (Redrawn from Wang et al. 2010. PDB kindly provided by Dr. Hao Wu.)
Figure 5.
Figure 5.
Model for the clustering of the CD95 receptor and FADD, based on the structure in Figure 4. The three different types of interface between different death domains (DDs) are shown by different lines. (Redrawn from Wang et al. 2010. PDB kindly provided by Dr. Hao Wu.)
Figure 6.
Figure 6.
Caspase-8 oligomerizes into filaments. (A) Domains in caspase-8. DED, death effector domain; Large, large subunit; Small, small subunit. (B) Cryoelectron microscopy structure of filament formed when caspase-8 prodomains are brought into proximity by FADD. Only death effector domain (DED) regions (1 and 2, colored as in A) are shown. (Left) “Top-down” view. (Right) Side view.
Figure 7.
Figure 7.
The CD95-induced apoptotic pathway, showing the principal players from the initial binding of the CD95 ligand (CD95-L) to the clustered receptors at the cell plasma membrane to formation of the death-inducing signaling complex (DISC), leading to eventual activation of executioner caspases.
Figure 8.
Figure 8.
FLIP inhibits apoptotic signaling. When FLICE-like inhibitory protein (FLIP) is present, the formation of the death-inducing signaling complex (DISC) recruits it, and this prevents caspase-8 from forming an active filament that would lead to apoptosis (as illustrated in Fig. 6). DED, death effector domain; FADD, FAS-associated DD protein.
Figure 9.
Figure 9.
Lymphoproliferative lpr disease. The mouse on the left carries the lpr mutation in the Cd95 (Fas) gene, resulting in massive enlargement of the lymphoid organs. The control mouse on the right is wild type. (Image courtesy of Dr. Ralph C. Budd, University of Vermont, Burlington.)
Figure 10.
Figure 10.
Tumor necrosis factor (TNF) signaling for NF-κB, antiapoptosis, and inflammation. Other proteins and modifications involved in the process are not shown.
Figure 11.
Figure 11.
The pathway of apoptosis induced by tumor necrosis factor (TNF). CYLD, ubiquitin carboxy-terminal hydrolase CYLD; DD, death domain; FADD, FAS-associated death domain protein; RIPK1, receptor-interacting serine/threonine-protein kinase 1; TRAF, TNF-receptor-associated factor; TRADD, tumor necrosis factor receptor type 1–associated death domain protein.
Figure 12.
Figure 12.
The pathway of death receptor signaling giving rise to mitochondrial outer membrane permeabilization (MOMP) through caspase-8-mediated cleavage of BID. TNF, tumor necrosis factor; FADD, FAS-associated DD protein; TRAF, TNF-receptor-associated factor; TRADD, tumor necrosis factor receptor type 1–associated DD protein.
Figure 13.
Figure 13.
Pathway of death receptor–induced apoptosis in type II cells. BID-induced mitochondrial outer membrane permeabilization (MOMP) can also engage apoptosome formation and caspase activation, but this does not appear to be necessary for apoptosis by this mechanism. DD, death domain.
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References

    1. Green DR. 2022a. Caspase activation and inhibition. Cold Spring Harb Perspect Biol 10.1101/cshperspect.a041020 - DOI - PMC - PubMed
    1. Green DR. 2022b. Nonapoptotic cell death pathways. Cold Spring Harb Perspect Biol 10.1101/cshperspect.a041079 - DOI - PMC - PubMed
    1. Green DR. 2022c. The mitochondrial pathway of apoptosis, Part II: the BCL-2 protein family. Cold Spring Harb Perspect Biol 10.1101/cshperspect.a041046 - DOI - PMC - PubMed

FIGURE CREDITS

    1. Banner DW, D'Arcy A, Janes W, Gentz R, Schoenfeld HJ, Broger C, Loetscher H, Lesslauer W. 1993. Crystal structure of the soluble human 55 kd TNF receptor-human TNF beta complex: implications for TNF receptor activation. Cell 73: 431–445. 10.1016/0092-8674(93)90132-a - DOI - PubMed
    1. Wang L, Yang JK, Kabaleeswaran V, Rice AJ, Cruz AC, Park AY, Yin Q, Damko E, Jang SB, Raunser S, et al. 2010. The Fas-FADD death domain complex structure reveals the basis of DISC assembly and disease mutations. Nat Struct Biol 17: 1324–1329. 10.1038/nsmb.1920 - DOI - PMC - PubMed

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