TNF receptor-associated death domain TRADD

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. 

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). 

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

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. 

For TRAF recruitment, since each receptor peptide contacts one TRAP domain only, avidity is the only factor that contributes to enhanced affinity of TRAFs for activated receptors. Due to the lack of structural information on DD interactions, it is not known whether ligand-induced receptor recruitment of FADD and TRADD (Hsu et al, 1996b) is also purely driven by avidity or the intracellular DD of the receptors also form composite binding sites for FADD and TRADD upon receptor activation. In keeping with the latter scenario, a protein known as silencer of death domains (SODD) (Jiang et al, 1999) has been shown to associate with the intracellular DD of TNF-Rl and get released upon ligand stimulation to activate the receptor. 

TNF is a proinflammatory cytokine produced mainly by macrophages. There are two main types of receptors, TNF-Rl and TNF-R2. TNF-R2 is primarily found in the immune system and is activated by membrane-bound TNF (Wajant et al., 2003). However, TNF-Rl, which is ubiquitously expressed, can be activated by both membrane-bound and soluble TNF. When TNF binds to the TNF receptor, TRADD (TNFRSFlA-associated via the death domain) is able to establish... 

The initial step in TNF-R1 activation involves the binding of the TNF trimer to TNF-Rl, resulting in receptor clustering and release of an inhibitory protein (silencer of death domains, SODD) from TNF-Rl s intracellular domain. Subsequently, the adaptor protein TRADD associates with the intracellular domain of the receptor and recruits additional adaptor proteins including FADD, which allows the binding and activation of caspase-8 within the TNF-R1 multiprotein complex. 

Fig. 15.11 Si gnaling by the tumor necrosis factor (TNF) receptor. Binding of TNF to its receptor induces association and activation for further signaling of several proteins which activate distinct signaling pathways. Assembly of the multiprotein complex on the cytoplasmic side is mediated mainly via death domains (DD) ofthe receptor and the adaptor protein TRADD. FADD induces apoptosis via activation of initiator caspase 8. TRAF2 and RIP mediate activation of transcription via two main ways. One way uses phosphorylation ofthe inhibitor IkB by IkB kinase (IKK) to induce its ubiquitin-mediated proteolytic destruction and the relieve ofNF cB inhibition. Another way leads to activation ofthe JNK pathway (see Chapter 10) and stimulation of transcription of diverse target genes.

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