TNF receptor-associated 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. 

TRADD TNF-receptor-associated death domain TNFRSF1A associated via death domain... 

Signalling for apoptosis can involve a plasma Fas ligand which binds to the PM Fas receptor with resultant activation of an associated cytosol-side Fas death domain of Fas and activation of caspase 8. Caspase 8 is a thiol protease and once activated initiates a so-called caspase cascade leading to activation of further caspases (with consequent proteolysis) and activation of a DNase (leading to DNA destruction with formation of a characteristic DNA fragment ladder ). Caspase 8 acts on mitochondria with resultant release of cytochrome c, which promotes caspase 3 activation by caspase 8 and hence the caspase cascade . Another signalling pathway for apoptosis involves tumour necrosis factor (TNF) binding to the TNF receptor with consequent activation of a cytosolic-side TNF receptor-associated death domain (TRADD) and resultant activation of the caspase cascade and cell death. 

TNF is a cytokine produced mainly by activated macrophages, and is the major extrinsic mediator of apoptosis. Most cells in the human body have two receptors for TNF TNF-Rl and TNF-R2. The binding of TNF to TNF-Rl has been shown to initiate the pathway that leads to caspase activation via the intermediate membrane proteins TNF receptor-associated death domain (TRADD) and Fas-associated death domain (FADD). The link between TNF and apoptosis shows why an abnormal production of TNF plays a fundamental role in several human diseases, especially autoimmune diseases (see Chapter 15). 

Yang QF, Huang W, Catherine J et al (2005) CGs inhibit TNF-a/NF-KB signaling by blocking recruitment of TNF receptor-associated death domain to the TNF receptor. Proc Natl Acad Sci USA 102 9631-9636... 

TNF-a is a membrane-bound protein that once cleaved may act as a cytokine similar in function to IL-1 (Malemud, 2004). TNF-a is proteolytically cleaved by MMPs then binds with TNF-Rl or TNF-R2, both found on osteoblasts and chondrocytes (Malemud, 2004) Once bound the TNF receptor and ligand complex form a trimer and begins the signaling pathway. TNF receptors associate with tumor necrosis factor receptor-associated death domain protein (TRADD) to initiate the signaling pathways through FADD and TRAF2/5 (Yoon and Fisher, 2007, Nanes, 2003). TRAF 2/5 lead to the activation of the NF-kB and MAPK pathways (Yoon and Fisher, 2007, Malemud, 2004, Nanes, 2003). The FADD pathway initiates apoptosis through the activation of the caspase pathway. 

There are two distinct types of TNF receptors, TNF-R1 (CD120a or P55) and TNF-R2 (CD120b or P75). They are implicated in inflammatory processes and both belong to the TNF receptor superfamily. TNF receptors are transmembrane proteins with intracellular domains that lack intrinsic enzymatic activity, and consequently, they require cytoplasmic proteins that help initiate the receptor-induced signaling pathways. TNF-R1 possesses an intracellular death domain and TNF-R2 interacts with molecules of the TNF receptor-associated factor 2 family (TRAF). 

Apoptosis PCR microarray is a relatively new methodology that uses real-time PCR to profile the expression of at least 112 key genes involved in apoptosis. The array includes the TNF ligands and their receptors members of the bcl-2, caspase, IAP, TRAF (TNF receptor associated factor), CARD (caspase activation and recruitment domain), death domain, death effector domain, and CIDE (cell death-inducing DFFA-like effector) families and genes involved in the p53 and ATM pathways. Also included in the evaluation are genes involved in anti-apoptosis. This assay allows for the evaluation of the expression of a focused panel of genes related to apoptosis. 

Death domain receptors. The cytokine TNF (tumor necrosis factor) uses a type of receptor called the death domain receptor (Fig. 11.21). These receptors function as a trimer when they bind TNF (which is also a trimer). On TNF binding, an inhibitory protein called the silencer of death is released from the receptor. The receptor then binds and activates several adaptor proteins. One adaptor protein, FADD (fas-associated death domain), recruits and activates the zymogen form of a proteolytic enzyme called caspase. Caspases... 

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