Death Receptors


Apoptosis, or programmed cell death, is a common property of all multicellular organisms and maintains essential cellular homeostasis in tissues by balancing cell renewal and removal of mutated or old cells. It can be triggered by a number of factors including ultraviolet (UV) or γ‐irradiation, chemotherapeutic drugs or growth factor withdrawal. A death signal can either be induced by the activation of death receptors (DRs, extrinsic pathway) or via the mitochondria (intrinsic pathway). The DR family is a subfamily of the tumour necrosis factor receptor (TNFR) superfamily. Stimulation of the DRs results in the formation of high‐molecular‐weight protein complexes that transduce apoptotic, necroptotic or survival signals.

Key Concepts

  • Stimulation of the death receptors (DRs) leads to apoptosis, necroptosis or NF‐κB activation.
  • All DRs are distinguished by the presence of the death domain (DD).
  • Cross‐linking of DR with death ligands results in the formation of the death‐inducing signalling complex (DISC).
  • Caspases play the central role in the transduction of DR‐induced apoptotic signal.
  • Procaspase‐8 is activated at the death effector domain (DED) chains at the DISC.
  • c‐FLIP proteins block or promote caspase‐8 activation at the DISC depending on their amount at the receptor complex and thereby regulate DR‐induced apoptosis.
  • Stimulation of DR might lead to the induction of receptor‐interacting protein kinase 1 and 3 (RIPK1‐ and RIPK3)‐mediated nonapoptotic cell death, necroptosis.
  • Apoptosis and necroptosis are triggered by high‐molecular‐weight protein complexes consisting of similar proteins.

Keywords: death receptors; caspase; death domain; apoptosis; necroptosis; NF‐κB

Figure 1. Death receptors. Death receptors and corresponding death ligands are shown. Death domains (DD) are shown in red. DR, death receptors; DcR, decoy receptors.
Figure 2. CD95 death‐inducing signalling complex (DISC). The DISC consists of CD95 (depicted in yellow), FAS‐associated death domain, FADD (depicted in light blue), and chains of procaspase‐8/procaspase‐10 (depicted in green), and cellular FLICE‐inhibitory proteins, c‐FLIP (depicted in magenta). The interactions between the molecules at the DISC are based on homotypic contacts. The death domain (DD) of CD95 interacts with the DD of FADD, whereas the death effector domain (DED) of FADD interacts with the N‐terminal tandem DEDs of procaspase‐8, procaspase‐10 and c‐FLIP. Procaspases‐8/10 and c‐FLIP form the DED chains at the DISC. DDs are shown in red; DEDs are shown in light green.
Figure 3. DR‐induced activation of apoptosis, necroptosis and NF‐κB. After stimulation of CD95/Fas/APO‐1 or TRAIL‐R1/2, the DISC forms at the membrane. The DISC comprises oligomerised DR, FADD and c‐FLIP/procaspase‐8/‐10 chains. Subsequently, complex II/Ripoptosome is formed in the cytosol. In both complexes, caspases‐8 and ‐10 are activated and induce the caspase cascade, which finally results in apoptosis. C‐FLIPL is processed into p43‐FLIP and activates the IKK (IκB kinase)‐complex. After phosphorylation and proteasomal degradation, the transcription factor NF‐κB (consisting of p65 homodimers) is free to translocate into the nucleus and to induce the expression of its target genes. In the absence of caspase activation, RIPK3 is recruited to the Ripoptosome to form the Necrosome. Here, several phosphorylation and autophosphorylation events lead to activation of RIPK1/RIPK3 and induce the necroptosis execution via RIPK3‐dependent activation of MLKL.
Figure 4. Scheme of c‐FLIP isoforms. The scheme represents three isoforms of c‐FLIP: c‐FLIPLong (c‐FLIPL), c‐FLIPShort (c‐FLIPS) and c‐FLIPRaji (c‐FLIPR). The p22 and p43 cleavage products result from the cleavage at D196 or D376, respectively, by caspase‐8/‐10. Death effector domain (DED) is presented in light green. Catalytically inactive caspase‐like domains of c‐FLIPL: p20 and p12 are indicated.


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Further Reading

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Zhang J, Yang Y, He W and Sun L (2016) Necrosome core machinery: MLKL. Cellular and Molecular Life Sciences 73: 2153–2163.

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Krammer, Peter H, Pietkiewicz, Sabine, and Lavrik, Inna N(Dec 2016) Death Receptors. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0021571.pub2]