Death receptor pathway

Mammals have evolved a mechanism that enables the organism to direct the death by apoptosis of unwanted cells (Ashkenazi and Dixit, 1998). The instructions for this altruistic suicide are provided by ligands such as tumour necrosis

Fig. 6.1. Overview of the main steps in signalling and execution of apoptosis.

factor (TNF) and Fas ligand (FasL or CD95L). Receptors for these death signals, found on the cell's plasma membrane, are encoded by genes that belong to the TNF receptor gene superfamily, and the best characterized of these are TNF receptor 1 (TNFR1) and Fas (also called CD95 and Apol) (Ashkenazi and Dixit, 1998). These receptors have both extracellular and cytoplasmic domains, with the latter acting as death domains (DDs). The sequence of events following binding of FasL or TNF to its respective receptor is subtly different (Ashkenazi and Dixit, 1998; Gupta, 2001), but the overall process is similar. FasL is an homotrimeric molecule, which, on binding to its receptor (three molecules of Fas), causes the clustering of the receptor's DD. This results in the binding of an adaptor protein called FADD (Fas-associated death domain), which in turn recruits procaspase-8 (the zymogen form of caspase-8; discussed below) (Ashkenazi and Dixit, 1998). The combination of the DD from Fas, FADD and procaspase-8 forms the death-inducing signalling complex (DISC), resulting in the activation of caspase-8 by the autocatalytic cleavage of procaspase-8 and so committing the cell to apoptosis (Gupta, 2001)

The Fas-FasL pathway of apoptosis is important in cellular immunity ensuring: (i) killing of

Fig. 6.2. Withdrawal of survival signals may initiate apoptosis.

target cells by cytotoxic T cells and natural killer (NK) cells; (ii) selection of T-cell repertoire and removal of self-recognizing T cells; (iii) deletion of activated lymphocytes when an immune response has been completed; and (iv) deletion of inflammatory/immune cells in 'immune privileged' tissues such as the testis and eye (Gupta, 2001). Mutations in either the Fas or the FasL gene are associated with autoimmune disorders (Lenardo et al., 1999).

TNF is secreted by activated macrophages and T cells in response to infection and, via binding to TNFR1, activates the transcription factors NF-kB and AP-1, resulting in the transcription of pro-inflammatory and immunomodulatory genes (Ashkenazi and Dixit, 1998; Gupta, 2001). However, if protein synthesis is inhibited, TNF triggers apoptosis. With the trimeric TNF bound to three molecules of TNFR1, the DDS of TNFR1 associate and recruit a group of signalling proteins including TRADD, FADD, TRAF-2 and RIP. The latter two proteins appear to be required for activation of NF-kB, whereas FADD is required for signalling of apoptosis via recruitment and activation of effector and regulatory caspases (Ashkenazi and Dixit, 1998; Gupta, 2001).

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