Death Receptor Signalling
Death receptors are cell surface receptors that transmit apoptotic signals initiated by specific ligands such as Fas ligand, TNF alpha and TRAIL. They play an important role in apoptosis and can activate a caspase cascade within seconds of ligand binding. Induction of apoptosis via this mechanism is therefore very rapid.
Although there are differences in the signalling pathways activated by the different death receptors it is possible to outline a general apoptotic signalling pathway, as seen in the animation below.
Binding of the death inducing ligand to its receptor can lead to a the generation of ceramide, typically produced by acid sphingomyelinase. This ceramide release is thought to promote lipid raft fusion which results in a large scale clustering of the death receptors. The large scale receptor clustering is important because it helps amplify the apoptotic signalling. In the absence of receptor clustering some cells, such as lymphocytes, are still able to trigger apoptosis but in most cases amplification of the signalling pathway is needed to activate the full apoptotic response.
Following ligand binding a conformational change in the intracellular domains of the receptors reveals the presence of a "death domain" which allows the recruitment of various apoptotic proteins to the receptor. This protein complex is often called the DISC, or Death Inducing Signalling Complex. The final step in this process is the recruitment of one of the caspases, typically caspase 8, to the DISC. This results in activation of caspase 8 and the inititation of apoptosis.
TNF is produced by T-cells and activated macrophages in response to infection. By activating its receptor, TNFR1, TNF can have several effects (see illustration below).
In some cells it leads to activation of NF-kB and AP-1 which leads to the induction of a wide range of genes. In some cells, however, TNF can also induce apoptosis, although receptor ligation is rarely enough on its own to initiate apoptosis as is the case with Fas ligand binding.
Binding of TNF alpha to TNFR1 results in receptor trimerisation and clustering of intracellular death domains. This allows binding of an intracellular adapter molecule called TRADD (TNFR-associated death domain) via interactions between death domains. TRADD has the ability to recruit a number of different proteins to the activated receptor. Recruitment of TRAF2 (TNF-associated factor 2) can lead to activation of NF-kB and the JNK pathway.
TRADD can also associate with FADD, which leads to the induction of apoptosis via the recruitment and cleavage of pro-caspase 8.
The ligand for Fas (FasL or CD95L) activated apoptosis in a similar way to the TNF receptor. Binding of the ligand promotes receptor clustering, DISC formation and the activation of the caspase cascade. However, signalling through the Fas receptor is slightly simpler than through the TNF receptor. The adapter protein FADD can be recruited directly to the death domain on the Fas receptor, without requiring the prior recruitment of TRADD. In addition the Fas receptor is generally though to only activate apoptosis and does not play an important role in other aspects of cell signalling like the TNF receptor.
In a number of ways TRAIL (TNF-related apoptosis inducing ligand) is similar in action to FasL. Binding of TRAIL to its receptors DR4 or DR5 triggers rapid apoptosis in many cells. Interestingly there are also decoy receptors that compete for binding of TRAIL with the DR4 and DR5 receptors. The decoy receptors are called DcR1 and DcR2. Both of these receptors are capable of competing with DR4 or DR5 receptors for binding to the ligand (TRAIL), however ligation of these receptors does not initiate apoptosis since DcR1 does not possess a cytoplasmic domain, while DcR2 has a truncated death domain lacking 4 out of 6 amino acids essential for recruiting adapter proteins.
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