Death ligand

The death ligand and the death receptor There is, on the surface of the cytotoxic T cell, a ligand that binds to a specific receptor on the infected cell known as a death receptor. The ligand is known as the FAS ligand (or death ligand). This binding results, via activation of intracellular proteases, in stimulation of the caspase system, which initiates apoptosis (Figure 17.31). (See Chapter 20 for description of apoptosis.)... 

Figure 17.31 Death of virally infected host celis via the death receptor on the host cell to which is bound the death ligand on the surface of the cytotoxic T-cell. The interaction between the ligand and the receptor results in activation of caspases that induce apoptosis. The latter process results in disintegration of the cell, the results of which are apoptotic vesicles that are phagocytosed and destroyed by the macrophages.

Figure 14-8. Overview of pathways that regulate programmed cell death. Apoptosis may occur in response to signaling through either the extrinsic pathway or the intrinsic pathway. In each case, proteolytic cleavage activates an initiator caspase, caspase 8 or 9, either of which can cleave an effector caspase such as caspase 3. Apaf-1 is part of a large complex called the apoptosome that mediates the intrinsic pathway. Binding of an extracellular death ligand to its cell-surface receptor activates the extrinsic pathway.

European researchers found recently that retinoic acid-induced apoptosis in leukemia cells was mediated by paracrine action of tumor-selective death ligand trail (tumor necrosis factor-related apoptosis-inducing ligand) [4]. 

The extrinsic pathway consists of a series of events initially induced by death receptors located on the cell surface. It is initiated by interaction of extracellular death ligands with their respective receptors, located on the surface of the plasma membrane. The death ligands are members of the tumor necrosis factor (TNF)/nerve growth factor (NGF) superfamily. TNF-R1, Fas (Apo-l/CD95), TRAIL-R1, TRAIL-R2, and NGF-R are examples of death receptors. They are transmembrane proteins consisting of an external domain, where the ligand associates, and a cytoplasmic domain, which contains the DD (death domain). 

Extrinsic (death receptor) pathway of caspase activation during apoptosis involves the binding of death ligands to cell surface receptors (e.g., Fas/ CD95/Apo-l or TNF receptor), recruitment of adaptor molecules Fas-associated death domain (FADD) or TNF receptor-associated death domain (TRADD) to the cytosolic end of the receptor, and formation of the death-inducing signaling complex (DISC) at the plasma membrane. DISC recruits and activates the initiator caspases, caspase-8 or -10. 

Many reports correlate the increased expression of caspases and the presence of cleaved caspases with certain types of degenerative diseases but the causal link has not been shown. For example, the increased expression of caspase-1, -2, -3, -5, -6, -7, -8, and -9 have been reported in AD (Chan and Mattson, 1999 LeBlanc et al., 1999 Lu et al., 2000 Pompl et al., 2003), caspases-3, -8 and -9 in PD (Anglade et al., 1997), caspases-1 and -3 in ALS (Pasinelli et al., 1998), and caspases-1 and -8 in HD (Sanchez et al., 1999). Altered expression levels of receptors and death ligands suggest a role for death pathways in these disorders. It has been reported that an increase in Fas expression may be harmful to both neurons and glia, and has been associated with neurodegeneration in diseases such as AD, PD, ALS, and HD (Barone and Parsons, 2000 Ugolini et al., 2003). 

The apoptotic machinery is controlled, like the cell cyde, by internal and external signals. External signals are received by receptors. The receptors that trigger apoptosis are called death receptors. Alfhou they may participate in other cellular signal transduction pathways, when they interact with death ligands they activate death effectors. The effectors are the caspases, a family of C5 teine proteases which eventually destroy the cell. 

Aktas O, Smorodchenko A, Brocke S, Infante-Duarte C, Top-phoff US, Vogt J, Prozorovski T, Meier S, Osmanova V, Pohl E, Bechmann I, Nitsch R, Zipp F (2005) Neuronal damage in autoimmune neuroinflammation mediated by the death ligand TRAIL. Neuron 46 421 32. 

Fig. 15.3 The major pathways of apoptosis. The extrinsic pathway uses extracellular death ligands (Fas ligand, tumor necrosis factor (TNF)) to activate death receptors which pass the apoptotic signal to initiator caspases (e. g. capsase 8) and to the executioner caspases (e. g. caspase 3 caspase 7). In the execution phase of apoptosis, various cellular substrates are degraded leading to cellular collapse. The intrinsic pathway uses the mitochondria as a central component for activation of apoptosis. In this pathway, a multitude of intracellular signals including various stresses, DNA damage and inappropriate cell signaling lead to activation of the pro-apoptotic protein Bax which induces release of cytochrome c from mitochindria, formation of the apoptosome and activation of the initiator caspase 9. Finally, the executioner caspases are activated and cells are destructed by proteolysis. Apoptosis via this pathway can be controlled by various antiapoptotic proteins including the Bcl-2 protein and inhibitors of apoptosis.

The activation of apoptosis via death receptors is a tightly regulated event. Soluble or membrane-bound decoy receptors can interfere with the death pathway by either scavenging the death ligand or by forming inactive mixed receptor complexes, thereby acting as dominant negative inhibitors. 

Chittenden T (2002) BH3 domains intracellular death-ligands critical for initiating apoptosis. Cancer Cell 2 165-166... 

The death receptors are a subset of TNF-1 receptors, which includes Fas/CD95, TNF-Receptor 1 (TNF-Rl) and Death Receptor 3 (DR3). These receptors form a trimer that binds TNF-1 or another death ligand on its external domain and adaptor proteins to its intracellular domain (Fig. 18.14). The activated TNF-receptor complex forms the scaffold for binding two molecules of procaspase 8, which autocatalytically cleave each other to form active caspase 8. Caspase 8 is an initiator caspase that activates execution caspases 3, 6, and 7. Caspase 8 also cleaves a Bcl-2 protein, Bid, to a form that activates the mitochondrial integrity pathway to apoptosis. 

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